Cinnamic acid amides

ABSTRACT

The present invention relates to compounds, to processes for preparing them, to pharmaceutical compositions comprising them, and to their use in the therapy and/or prophylaxis in illnesses in people or animals, especially diseases of bacterial infection.

The present invention relates to compounds, to processes for preparingthem, to pharmaceutical compositions comprising them, and to their usein the therapy and/or prophylaxis in illnesses in people or animals,especially diseases of bacterial infection.

The natural substances moiramide B (R^(a)=hydrogen, R^(b)=methyl) andandrimid (R^(a)=hydrogen, R^(b)=propenyl) have been described as havingantibacterial activity, whereas moiramide C (R^(a)=hydroxyl,R^(b)=propenyl) is inactive. (A. Fredenhagen, S. Y. Tamura, P. T. M.Kenny, H. Komura, Y. Naya, K. Nakanishi, J. Am. Chem. Soc., 1987, 109,4409-4411; J. Needham, M. T. Kelly, M. Ishige, R. J. Andersen, J. Org.Chem., 1994, 59, 2058-2063; M. P. Singh, M. J. Mroczenski-Wildey, D. A.Steinberg, R. J. Andersen, W. M. Maiese, M. Greenstein, J. Antibiot.,1997, 50(3), 270-273). The isolation and antibacterial activity ofandrimid is also described in EP-A-250 115. JP 01301657 describes theuse of andrimid and certain amide-type derivatives as agrochemicalantibiotics.

The synthesis of andrimid is described in A. V. Rama Rao, A. K. Singh,Ch. V. N. S. Varaprasad, Tetrahedron Letters, 1991, 32, 4393-4396, thatof moiramide B and andrimid in S. G. Davies, D. J. Dixon, J. Chem. Soc.,Perkin Trans. 1, 1998, 2635-2643.

The properties of the natural substances, such as their activity, forexample, do not meet the requirements imposed on antibacterial medicinalproducts.

Although antibacterial products with different structures are on themarket, a regular possibility is the development of resistance. Newproducts for improved and effective therapy are therefore desirable.

It is an object of the present invention, therefore, to provide new andalternative compounds having equal or improved antibacterial action fortreating bacterial diseases in people and animals.

Surprisingly it has been found that derivatives of this class ofcompound in which the beta-phenylalanine amide group is replaced by avinylogous aromatic or heteroaromatic amide have antibacterial activity.

The present invention accordingly provides compounds of the formula

in which

-   R¹ is hydrogen, methyl or halogen,-   R^(1′) is hydrogen, methyl or halogen,-   R² is hydrogen or methyl,-   R³ is hydrogen, hydroxyl, amino, C₁-C₃ alkyl, C₁-C₃ alkoxy,    benzyloxy, C₁-C₃ alkylamino, C₁-C₃ alkylcarbonylamino,    phenylcarbonylamino or benzyl-carbonylamino,-   R⁴ is hydrogen or C₁-C₃ alkyl,-   R⁵ is halogen, trifluoromethyl, trifluoromethoxy, nitro, amino,    alkylamino, hydroxyl, alkyl, alkoxy, carboxyl, alkoxycarbonyl,    benzyloxycarbonyl, aminocarbonyl, alkylaminocarbonyl, aryl or    heteroaryl,    or    two substituents R⁵ together with the carbon atoms to which they are    attached form a cycloalkyl or heterocyclyl each of which may be    substituted by 0, 1 or 2 substituents R⁵⁻¹, the substituents R⁵⁻¹    being selected independently of one another from the group    consisting of halogen, nitro, amino, trifluoromethyl, hydroxyl and    alkoxy,-   R⁶ is alkyl, cycloalkyl or cycloalkenyl,    it being possible for R⁶ to be substituted by 0, 1, 2 or 3    substituents R⁶⁻¹, the substituents R⁶⁻¹ being selected    independently of one another from the group consisting of halogen,    nitro, amino, trifluoromethyl, hydroxyl, alkyl and alkoxy,-   n is a number 0, 1, 2 or 3,    it being possible for the radicals R⁵ to be identical or different    when n is 2 or 3,-   m is a number 1, 2 or 3,-   A is aryl or heteroaryl,    it being possible for A to be substituted by 0, 1, 2 or 3    substituents R^(A), the substituents R^(A) being selected    independently of one another from the group consisting of halogen,    alkyl, nitro, amino, cyano, trifluoromethyl, aryl, heteroaryl,    hydroxyl, alkoxy, alkylamino, carboxyl, alkoxycarbonyl,    aminocarbonyl, alkyl-carbonylamino and alkylaminocarbonyl,    or    two substituents R^(A) together with the carbon atoms to which they    are attached form a cycloalkyl or heterocyclyl each of which may be    substituted by 0, 1 or 2 substituents R^(A-1), the substituents    R^(A-1) being selected independently of one another from the group    consisting of halogen, nitro, amino, trifluoromethyl, hydroxyl and    alkoxy,-   B is aryl or heteroaryl.

The compounds of the invention may also be in the form of their salts,solvates or solvates of the salts.

Depending on their structure the compounds of the invention may exist instereoisomeric forms (enanfromers, diastereomers). The inventiontherefore relates to the enantiomers or diastereomers and theirrespective mixtures. From such mixtures of enantiomers and/ordiastereomers it is possible to isolate the stereoisomerically uniformconstituents in a known way.

The invention relates also, depending on the structure of the compounds,to tautomers of the compounds.

Salts preferred in the context of the invention are physiologicallyacceptable salts of the compounds of the invention.

Physiologically acceptable salts of the compounds (I) embrace acidaddition salts of mineral acids, carboxylic acids and sulfonic acids,e.g., salts of hydrochloric acid, hydrobromic acid, sulfuric acid,phosphoric acid, methanesulfonic acid, ethanesulfonic acid,toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid,acetic acid, propionic acid, lactic acid, tartaric acid, malic acid,citric acid, fumaric acid, maleic acid and benzoic acid.

Physiologically acceptable salts of the compounds (I) also embrace saltsof customary bases, such as, by way of example and preferably, alkalimetal salts (e.g., sodium and potassium salts), alkaline earth metalsalts (e.g. calcium and magnesium salts) and ammonium salts derived fromammonia or organic amines having 1 to 16 carbon atoms, such as, by wayof example and preferably, ethylamine, diethylamine, triethylamine,ethyldiisopropylamine, monoethanolamine, diethanolamine,triethanolamine, dicyclo-hexylamine, dimethylaminoethanol, procaine,dibenzylamine, n-methylmorpholine, dihydroabietylamine, arginine,lysine, ethylenediamine and methylpiperidin.

Solvates in the context of the invention are those forms of thecompounds which in the solid or liquid state form a complex bycoordination with solvent molecules. Hydrates are one specific form ofthe solvates, in which the coordination is with water.

In the context of the present invention the signification of thesubstituents, unless specified otherwise, is as follows

Alkyl per se and “alk” and “alkyl” in alkoxy alkylamino,alklaminocarbonyl, alkylcarbonylamino and alkoxycarbonyl are a linear orbranched alkyl radical having generally 1 to 6, preferably 1 to 4,more-preferably 1 to 3 carbon atoms, by way of example and preferablymethyl, ethyl, n-propyl, isopropyl, tert-butyl, n-pentyl and n-hexyl.

Alkoxy is by of example and preferably methoxy, ethoxy, n-propoxy,isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy.

Alkylamino is an alkylamino radical having one or two alkyl substituents(chosen independently of one another), by way of example and preferablymethylamino, ethylamino, n-propylamino, isopropylamino, tert-butylamino,n-pentylamino, n-hexylamino, N,N-dimethylamino, N,N-diethylamino,N-ethyl-N-methylamino, N-methyl-N-n-propylamino,N-isopropyl-N-n-propylamino, N-t-butyl-N-methylamino,N-ethyl-N-n-pentylamino and N-n-Hexyl-N-methylamino.

Alkylaminocarbonyl is an alkylaminocarbonyl radical having one or twoalkyl substituents (chosen independently of one another), by way ofexample and preferably methylaminocarbonyl, ethylaminocarbonyl,n-propylaminocarbonyl, isopropylamino-carbonyl, tert-butylaminocarbonyl,n-pentylaminocarbonyl, n-hexylaminocarbonyl, N,N-dimethylaminocarbonyl,N,N-diethylaminocarbonyl, N-ethyl-N-methylamino-carbonyl,N-methyl-N-n-propylaminocarbonyl, N-isopropyl-N-n-propylaminocarbonyl,N-t-butyl-N-methylaminocarbonyl, N-ethyl-N-n-pentylaminocarbonyl andN-n-hexyl-N-methylaminocarbonyl.

Alkylcarbonylamino is by way of example and preferablymethylcarbonylamino, ethylcarbonylamino, n-propylcarbonylamino,isopropylcarbonylamino, tert-butyl-carbonylamino, n-pentylcarbonylaminoand n-hexylcarbonylamino.

Alkoxycarbonyl is by way of example and preferably methoxycarbonyl,ethoxy-carbonyl, n-propoxycarbonyl, isopropoxycarbonyl,tert-butoxycarbonyl, n-pentoxycarbonyl and n-hexoxycarbonyl.

Cycloalkyl is a cycloalkyl group having generally 3 to 8, preferably 5to 7 carbon atoms; specified by way of example and preferably forcycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl andcycloheptyl.

Cycloalkenyl is a cycloalkyl group having generally 3 to 8, preferably 5to 7 carbon atoms; specified by way of example and preferably forcycloalkenyl are cyclopropenyl, cyclobutenyl, cyclopentenyl,cyclohexenyl and cycloheptenyl.

Aryl is a mono- to tricyclic aromatic radical having generally 6 to 14carbon atoms; specified by way of example and preferably for aryl arephenyl, naphthyl and phenanthrenyl.

Heteroaryl is an aromatic, mono- or bicyclic radical having generally 5to 10, preferably 5 to 6 ring atoms and up to 5, preferably up to 4,heteroatoms from the series S, O and N; by way of example and preferablythienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyridyl,pyrimidyl, pyridazinyl, indolyl, indazolyl, benzofuranyl,benzothiophenyl, quinolinyl, isoquinolinyl.

Heterocyclyl is a mono- or polycyclic, preferably mono- or bicyclic,heterocyclic radical having generally 4 to 10, preferably 5 to 8 ringatoms and up to 3, preferably up to 2, heteroatoms and/or hetero-groupsfrom the series N, O, S, SO, SO₂. The heterocyclyl radicals may besaturated or partly unsaturated. Preference is given to 5- to8-membered, monocyclic saturated heterocyclyl radicals having up to twoheteroatoms from the series O, N and S, such as, by way of example andpreferably, tetrahydrofuran-2-yl, pyrrolidin-2-yl, pyrrolidin-3-yl,pyrrolinyl, piperidinyl, morpholinyl, perhydroazepinyl.

Halogen is fluorine, chlorine, bromine and iodine, preferably fluorineand chlorine.

If radicals in the compounds of the invention are substituted theradicals, unless specified otherwise, may be substituted by one or moreidentical or different substituents. Substitution by up to threeidentical or different substituents is preferred. Very particularpreference is given to substitution by one substituent.

Preference is given in the context of the present invention to compoundsof the formula (I)

in which

-   R¹ is hydrogen or methyl,-   R^(1′) is hydrogen, methyl or fluorine,-   R² is hydrogen,-   R³ is hydrogen, amino, C₁-C₃ alkyl, C₁-C₃ alkoxy, benzyloxy, C₁-C₃    alkylamino, C₁-C₃ alkylcarbonylamino, phenylcarbonylamino or    benzyl-carbonylamino,-   R⁴ is methyl,-   R⁵ is fluorine, chlorine, trifluoromethyl, trifluoromethoxy, nitro,    amino, alkylamino, hydroxyl, alkyl, alkoxy, alkoxycarbonyl,    aminocarbonyl, phenyl or 5- to 6-membered heteroaryl,    or    two substituents R⁵ together with the carbon atoms to which they are    attached form a 5- to 6-membered cycloalkyl or 5- to 6-membered    heterocyclyl,-   R⁶ is C₂-C₇ alkyl, C₃-C₇ cycloalkyl or C₅-C₇ cycloalkenyl,    it being possible for R⁶ to be substituted by 0, 1 or 2 substituent    R⁶⁻¹, R⁶⁻¹ being selected from the group consisting of halogen,    trifluoromethyl, alkyl and methoxy,-   n is a number 0, 1 or 2,    it being possible for the radicals R⁵ to be identical or different    if n is 2,-   m is a number 1 or 2,-   A is phenyl, naphthyl or 5-, 6- or 10-membered heteroaryl,    it being possible for A to be substituted by 0, 1 or 2 substituents    R^(A), the substituents R^(A) being selected independently of one    another from the group consisting of halogen, alkyl, amino, cyano,    trifluoromethyl, aryl, heteroaryl, hydroxyl, alkoxy, alkylamino,    alkoxycarbonyl and aminocarbonyl,    or    two substituents R^(A) together with the carbon atoms to which they    are attached form a 5- to 6-membered cycloalkyl or 5- to 6-membered    heterocyclyl each of which may be substituted by 0 or 1 substituents    R^(A-1), the substituents R^(A-1) being selected independently of    one another from the group consisting of halogen, nitro, amino,    trifluoromethyl, hydroxyl and alkoxy,    B is phenyl, naphthyl or 5-, 6-, 9- or 10-membered heteroaryl.

Preference in the context of the present invention is also given tocompounds of the formula (I) which conform to the formula (Ia)

in which

-   R¹ is hydrogen,-   R^(1′) is hydrogen, methyl or fluorine,-   R² is hydrogen,-   R³ is hydrogen, amino, methyl, methoxy, ethoxy, methylamino or    dimethylamino,-   R⁴ is methyl,-   R⁵ is fluorine, chlorine, trifluoromethyl, alkoxy, methoxycarbonyl,    C₁-C₄ alkyl, phenyl or pyridyl,    or    two substituents R⁵ together with the carbon atoms to which they are    attached form a 5- or 6-membered heterocyclyl,-   R⁶ is C₃-C₆ alkyl, C₄-C₆ cycloalkyl or C₅-C₆ cycloalkenyl,-   n is a number 0, 1 or 2,    it being possible for the radicals R⁵ to be identical or different    if n is 2,-   m is the number 1,-   A is phenyl, pyridyl, imidazolyl, thienyl, furanyl, oxadiazolyl,    pyrazolyl, pyrazinyl, pyridazinyl, pyrimidinyl, quinolinyl or    isoquinolinyl,    it being possible for A to be substituted by 0, 1 or 2 substituents    R^(A), the substituents R^(A) being selected independently of one    another from the group consisting of halogen, alkyl, cyano,    trifluoromethyl, phenyl and alkoxy,    or    two substituents R^(A) together with the carbon atoms to which they    are attached form a 5- or 6-membered heterocyclyl,-   B is phenyl, naphthyl, pyridyl, thienyl, furanyl, quinolinyl or    isoquinolinyl. Preference in the context of the present invention is    also given to compounds of the formula (Ia),    in which-   R¹ is hydrogen,-   R^(1′) is hydrogen,-   R² is hydrogen,-   R³ is hydrogen, amino, methylamino or dimethylamino,-   R⁴ is methyl,-   R⁵ is fluorine, chlorine, trifluoromethyl, methoxy, C₁-C₆ alkyl,    phenyl or pyridyl,    or    two substituents R⁵ together with the phenyl ring to which they are    attached form a 1,3-benzodioxole or a 1,4-benzodioxane,-   R⁶ is isopropyl, tert-butyl, isobutyl, isopentyl, cyclobutyl or    cyclopentyl,-   n is a number 0, 1 or 2,    it being possible for the radicals R⁵ to be identical or different    if n is 2,-   m is the number 1,-   A is phenyl, pyridyl, thienyl, quinolinyl or isoquinolinyl,    it being possible for A to be substituted by 0, 1 or 2 substituents    R^(A), the substituents R^(A) being selected independently of one    another from the group consisting of fluorine, chlorine, C₁-C₃    alkyl, cyano, trifluoromethyl, phenyl and C₁-C₃ alkoxy,    or    two substituents R^(A) together with the phenyl ring to which they    are attached form a 1,3-benzodioxole or a 1,4-benzodioxane,-   B is phenyl, naphthyl, thienyl, quinolinyl or isoquinolinyl.

Preference in the context of the present invention is also given tocompounds of formula (I) in which R¹ to R⁶, A, B, m and n are as definedabove and R⁴ is other than hydrogen.

Preference in the context of the present invention is also given to thecompounds of the formula (I) in which R¹ is hydrogen.

Preference in the context of the present invention is also given to thecompounds of the formula (I) or (Ia) in which R^(1′) is hydrogen.

Preference in the context of the present invention is also given to thecompounds of the formula (I) in which R² is hydrogen.

Preference in the context of the present invention is also given to thecompounds of the formula (I) or (Ia) in which R³ is hydrogen or amino.

Preference in the context of the present invention is also given to thecompounds of the formula (I) in which R⁴ is methyl.

Preference in the context of the present invention is also given to thecompounds of the formula (I) or (Ia) in which n is the number zero.

Preference in the context of the present invention is also given to thecompounds of the formula (I) in which n is the number 1, B is phenyl andR⁵ is fluorine, chlorine, trifluoromethyl, alkoxy, C₁-C₄ alkyl, phenylor pyridyl, R⁵ being positioned meta or para to the linkage site of thephenyl ring. By the linkage site of the phenyl ring is meant the carbonatom of the phenyl ring carrying R⁵ to which the phenyl ring carryingR⁵, in accordance with formula (I) or (Ia) as B, is attached to theremainder of the compound.

Preference in the context of the present invention is also given to thecompounds of the formula (I) or (Ia), in which R⁶ is isopropyl,tert-butyl, isobutyl, isopentyl or cyclopentyl.

Preference in the context of the present invention is also given to thecompounds of the formula (I), in which m is the number 1.

Preference in the context of the present invention is also given to thecompounds of the formula (I) or (Ia) in which

-   A is phenyl or pyridyl,    it being possible for A to be substituted by 0, 1 or 2 substituents    R^(A), the substituents R^(A) being selected independently of one    another from the group consisting of fluorine, chlorine, cyano,    trifluoromethyl, phenyl and methoxy.

Preference in the context of the present invention is also given to thecompounds of the formula (I) or (Ia) in which B is phenyl.

Preference in the context of the present invention is also given to thefollowing compounds:

-   (2E)-3-(1,3-benzodioxol-5-yl)-N-{(1S)-3-[((1S)-2-methyl-1-{[(3R,4S)-4-methyl-2,5-dioxo-3-pyrrolidinyl]carbonyl}propyl)amino]-3-oxo-1-phenylpropyl}-2-propenamide,-   (2E)-3-(1,3-benzodioxol-5-yl)-N-{(1S)-3-[((1S)-2,2-dimethyl-1-{[(3R,4S)-4-methyl-2,5-dioxo-3-pyrrolidinyl]carbonyl}propyl)amino]-3-oxo-1-phenylpropyl}-2-propenamide,-   (2E)-3-(1,3-benzodioxol-5-yl)-N-{1-(2,3-dihydro-1,4-benzodioxin-6-yl)-3-[((1S)-2-methyl-1-{[(3R,4S)-4-methyl-2,5-dioxo-3-pyrrolidinyl]carbonyl}propyl)amino]-3-oxopropyl}-2-propenamide,-   (2E)-N-{1-(2,3-dihydro-1,4-benzodioxin-6-yl)-3-[((1S)-2-methyl-1-{[(3R,4S)-4-methyl-2,5-dioxo-3-pyrrolidinyl]carbonyl}propyl)amino]-3-oxopropyl}-3-phenyl-2-propenamide,-   (2E)-N-{(1S)-3-[((1S)-2-methyl-1-{[(3R,4S)-4-methyl-2,5-dioxo-3-pyrrolidinyl]-carbonyl}propyl)amino]-3-oxo-1-phenylpropyl}-3-(4-methylphenyl)-2-propenamide,-   (2E)-3-(2H-benzo[d]1,3-dioxolan-5-yl)-N-((1S)-2-{N-[(1S)-2-((4S,3R)-4-methyl-2,5-dioxoazolidin-3-yl)-1-cyclopentyl-2-oxoethyl]carbamoyl}-1-phenylethyl)prop-2-enamide,-   (2E)-N-((1S)-2-{N-[(1S)-2-((4S,3R)-4-methyl-2,5-dioxoazolidin-3-yl)-1-cyclopentyl-2-oxoethyl]carbamoyl}-1-phenylethyl)-3-(4-cyanophenyl)prop-2-enamide,-   (2E)-N-((1S)-2-{N-[(1S)-2-((4S,3R)-1-amino-4-methyl-2,5-dioxoazolidin-3-yl)-1-cyclopentyl-2-oxoethyl]carbamoyl}-1-phenylethyl)-3-(4-cyanophenyl)prop-2-en-amide,-   (2E)-N-(2-{N-[(1S)-2-((4S,3R)-1-amino-4-methyl-2,5-dioxoazolidin-3-yl)-1-cyclo-pentyl-2-oxoethyl]carbamoyl}-1-(2-naphthyl)ethyl)-3-(4-cyanophenyl)prop-2-en-amide,-   (2E)-N-[(1S)-2-(N-{(1S)-2-[(4S,3R)-1-(dimethylamino)-4-methyl-2,5-dioxoazolidin-3-yl]-1-cyclopentyl-2-oxoethyl}carbamoyl)-1-phenylethyl]-3-(4-cyanophenyl)prop-2-enamide.

The invention further provides processes for preparing compounds of theformula (I), where

by process [A]compounds of the formula

in which R² to R⁶, B and n are as defined above, are reacted withcompounds of the formula

in which R¹ and R^(1′), A and m are as defined above,it being possible for these to be in activated form if desired,orby process [B]compounds of the formula

in which R³, R⁴ and R⁶ are as defined above,are reacted with compounds of the formula

in which R¹, R^(1′), R², R⁵, A, B, m and n are as defined above,it being possible for these to be in activated form if desired.

Suitable for converting the compounds into the activated form in theabove-mentioned processes are, for example, carbodiimides such asN,N′-diethyl-, N,N′,-dipropyl-, N,N′-diisopropyl-,N,N′-dicyclohexylcarbodiimide,N-(3-dimethylaminoisopropyl)-N′-ethylcarbodiimide hydrochloride (EDC)(optionally in the presence of pentafluorophenol (PFP)),N-cyclohexylcarbodiimide-N′-propyloxymethyl-polystyrene(PS-carbodiimide) or carbonyl compounds such as carbonyldiimidazole, or1,2-oxazolium compounds such as 2-ethyl-5-phenyl-1,2-oxazolium-3-sulfateor 2-tert-butyl-5-methyl-isoxazolium perchlorate, or acylamino compoundssuch as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, orpropanephosphonic anhydride, or isobutyl chloroformate, orbis(2-oxo-3-oxazolidinyl)phosphoryl chloride orbenzotriazolyloxytri(dimethylamino)phosphonium hexafluorophosphate, orO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU), 2-(2-oxo-1-(2H)-pyridyl)-1,1,3,3-tetramethyluroniumtetrafluoroborate (TPTU) orO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyl-uroniumhexafluorophosphate (HATU), or 1-hydroxybenzotriazole (HOBt), orbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(BOP), or mixtures of these with bases.

Bases are, for example, alkali metal carbonates, such as sodium orpotassium carbonate, or hydrogencarbonate, or organic bases such astrialkylamines, e.g. triethylamine, N-methylmorpholine,N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine.

Preference is given to using HATU and diisopropylethylamine or EDC withHOBt and triethylamine.

Suitable solvents in this context include inert organic solvents whichdo not change under the reaction conditions. These include halogenatedhydrocarbons such as dichloromethane or trichloromethane, hydrocarbonsuch as benzene, xylene, toluene, hexane, cyclohexane, or petroleumfractions, nitromethane, dimethylformamide or acetonitrile or etherssuch as diethyl ether, tetrahydrofuran or dioxane. It is also possibleto use mixtures of the solvents. Particular preference is given to amixture of dichloromethane and dimethylformamide.

Process [A]

The compounds of the formula (II) are known or can be prepared byadmixing compounds of the formula

in which R² to R⁶, B and n are as defined above,with acid, in particular with hydrochloric acid or trifluoroacetic acid.The compounds of the formula (II) are in this case obtained in the formof the corresponding salts, e.g. in the form of their hydrochlorides,and can be used further in this form.

Suitable solvents in this context include inert organic solvents whichdo not change under the reaction conditions. These include halogenatedhydrocarbons such as dichloromethane or trichloromethane, hydrocarbonssuch as benzene, xylene, toluene, hexane, cyclohexane, or petroleumfractions, nitromethane, dimethylformamide or acetonitrile or etherssuch as diethyl ether, tetrahydrofuran or dioxane. It is also possibleto use mixtures of the solvents. Particular preference is given to theuse of hydrochloric acid in dioxane or trifluoroacetic acid indichloromethane.

The compounds of the formula (VI) are known or can be prepared byreacting compounds of the formula (IV) with compounds of the formula

in which R², R⁵, B and n are as defined above,it being possible for these to be in activated form if desired.

Suitable for converting the compounds into the activated form are, forexample, carbodiimides such as N,N′-diethyl-, N,N′,-dipropyl-,N,N′-diisopropyl-, N,N′-dicyclohexylcarbodiimide,N-(3-dimethylaminoisopropyl)-N′-ethylcarbodiimide hydrochloride (EDC)(optionally in the presence of pentafluorophenol (PFP)),N-cyclohexylcarbodiimide-N′-propyloxymethyl-polystyrene(PS-carbodiimide) or carbonyl compounds such as carbonyldiimidazole, or1,2-oxazolium compounds such as 2-ethyl-5-phenyl-1,2-oxazolium-3-sulfateor 2-tert-butyl-5-methyl-isoxazolium perchlorate, or acylamino compoundssuch as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, orpropanephosphonic anhydride, or isobutyl chloroformate, orbis(2-oxo-3-oxazolidinyl)phosphoryl chloride orbenzotriazolyloxytri(dimethylamino)phosphonium hexafluorophosphate, orO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU), 2-(2-oxo-1-(2H)-pyridyl)-1,1,3,3-tetramethyluroniumtetrafluoroborate (TPTU) orO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyl-uroniumhexafluorophosphate (HATU), or 1-hydroxybenzotriazole (HOBt), orbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(BOP), or mixtures of these with bases.

Bases are, for example, alkali metal carbonates, such as sodium orpotassium carbonate, or hydrogencarbonate, or organic bases such astrialkylamines, e.g. triethylamine, N-methylmorpholine,N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine.

Preference is given to using HATU and diisopropylethylamine or EDC withHOBt and triethylamine.

Suitable solvents in this context include inert organic solvents whichdo not change under the reaction conditions. These include halogenatedhydrocarbons such as dichloromethane or trichloromethane, hydrocarbonsuch as benzene, xylene, toluene, hexane, cyclohexane, or petroleumfractions, nitromethane, dimethylformamide or acetonitrile or etherssuch as diethyl ether, tetrahydrofuran or dioxane. It is also possibleto use mixtures of the solvents. Particular preference is given to amixture of dichloromethane and dimethylformamide.

The compounds of the formula (IV) are known from the literature or canbe prepared by admixing compounds of the formula

in which R³, R⁴ and R⁶ are as defined above,with acid, in particular with hydrochloric acid or trifluoroacetic acid.

Suitable solvents in this context include inert organic solvents whichdo not change under the reaction conditions. These include halogenatedhydrocarbons such as dichloromethane or trichloromethane, hydrocarbonssuch as benzene, xylene, toluene, hexane, cyclohexane, or petroleumfractions, nitromethane, dimethylformamide or acetonitrile or etherssuch as diethyl ether, tetrahydrofuran or dioxane. It is also possibleto use mixtures of the solvents. Particular preference is given to theuse of hydrochloric acid in dioxane or trifluoroacetic acid indichloromethane.

The compounds of the formula (VII) are known or can be prepared byprocedures known from the literature. (With regard to the preparation ofaromatic beta-amino acids see: S. Rault, P. Dallemagne, M. Robba, Bull.Soc. Chim. Fr., 1987, 1079-1083; S. G. Davies, et al., J. Chem. Soc.,Chem. Commun. 1993, 14, 1153-1155; regarding the reaction to form thetert-butoxycarbonyl-protected compounds see T. W. Greene, P. G. M. Wuts,Protective Groups in Organic Synthesis, 3^(rd) Edt. 1999, J. Wiley &Sons, Inc.).

The compounds of the formula (VIII) are known or can be prepared bymethods known from the literature. (Cf., e.g., S. G. Davies, D. J.Dixon, J. Chem. Soc., Perkin Trans. 1, 1998, 17, 2635-2643; A. V. RamaRao, A. K. Singh, Ch. V. N. S. Varaprasad, Tetrahedron Letters, 1991,32, 4393-4396).

The compounds of the formula (III) are known or can be prepared bymethods known from the literature (Houben-Weyl, Methoden der organischenChemie, vol. E5, carboxylic acids and carboxylic acid derivatives,Thieme Verlag, Stuttgart, 1985).

Process [B]

The compounds of the formula (V) are known from the literature or can beprepared by hydrolyzing compounds of the formula

in which R¹, R^(1′), R², R⁵, A, B, m and n are as defined above and R⁷is an alkyl radical.

The hydrolysis can be carried out in accordance with standard methods,e.g., in a mixture of ethanol and water with 40% strength sodiumhydroxide solution at room temperature or in a mixture of dioxane andwater with methanolic potassium hydroxide solution.

The compounds of the formula (IX) are known from the literature or canbe prepared by reacting compounds of the formula

in which R², R⁵, R⁷, B and n are as defined above,with compounds of the formula (III), it being possible for these to bein activated form if desired.

Suitable for converting the compounds into the activated form in theabovementioned processes are, for example, carbodiimides such asN,N′-diethyl-, N,N′,-dipropyl-, N,N′-diisopropyl-,N,N′-dicyclohexylcarbodiimide,N-(3-dimethylaminoisopropyl)-N′-ethylcarbodiimide hydrochloride (EDC)(optionally in the presence of pentafluorophenol (PFP)),N-cyclohexylcarbodiimide-N′-propyloxymethyl-polystyrene(PS-carbodiimide) or carbonyl compounds such as carbonyldiimidazole, or1,2-oxazolium compounds such as 2-ethyl-5-phenyl-1,2-oxazolium-3-sulfateor 2-tert-butyl-5-methyl-isoxazolium perchlorate, or acylamino compoundssuch as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, orpropanephosphonic anhydride, or isobutyl chloroformate, orbis(2-oxo-3-oxazolidinyl)phosphoryl chloride orbenzotriazolyloxytri(dimethylamino)phosphonium hexafluorophosphate, orO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU), 2-(2-oxo-1-(2H)-pyridyl)-1,1,3,3-tetramethyluroniumtetrafluoroborate (TPTU) orO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyl-uroniumhexafluorophosphate (HATU), or 1-hydroxybenzotriazole (HOBt), orbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(BOP), or mixtures of these with bases.

Bases are, for example, alkali metal carbonates, such as sodium orpotassium carbonate, or hydrogencarbonate, or organic bases such astrialkylamines, e.g. triethylamine, N-methylmorpholine,N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine.

Preference is given to using HATU and diisopropylethylamine or EDC withHOBt and triethylamine.

Suitable solvents in this context include inert organic solvents whichdo not change under the reaction conditions. These include halogenatedhydrocarbons such as dichloromethane or trichloromethane, hydrocarbonsuch as benzene, xylene, toluene, hexane, cyclohexane, or petroleumfractions, nitromethane, dimethylformamide or acetonitrile or etherssuch as diethyl ether, tetrahydrofuran or dioxane. It is also possibleto use mixtures of the solvents. Particular preference is given to amixture of dichloromethane and dimethylformamide.

The compounds of the formula (X) are known from the literature or can beprepared in analogy to methods known from the literature (e.g., S. G.Davies et. al., J. Chem. Soc. Chem. Comm., 1993, 14, 1153-1155; S. J.Faulconbridge et al., Tetrahedron Letters, 2000, 41, 2679-2682; M. J.Ashton et al., Heterocycles, 1989, 28, 1015-1035).

Synthesis may also take place on a polymeric support. In that case R² inthe synthesis sequence is a polymer (Resin), preference being given tothe use of 4-(4-formyl-3-methoxyphenoxy)butyryl-aminomethyl-polystyreneor another resin in which a polymeric backbone such as polystyrene orblock copolymers of polystyrene with ethylene glycol has attached to itvia a linker group such as 3-methoxyphenoxyethyl,3,5-dimethoxyphenoxyethoxymethyl or 3-methoxyphenoxybutyrylaminomethyl aformyl radical or another radical which allows amines to be attached tothe polymeric support.

The preparation of the compounds of the invention can be illustrated bythe following synthesis schemes:

Starting Compounds:

PREPARATION EXAMPLES Method A

Method B

Solid-Phase Synthesis:

The present invention further provides compounds of the formula (I) forcontrolling diseases, particularly bacterial diseases, and alsomedicinal products comprising compounds of the formula (I) incombination with at least one pharmaceutically compatible,pharmaceutically acceptable carrier or other auxiliary, and also for theuse of compounds of the formula (I) for producing a medicinal productfor treating bacterial diseases.

The formulations of the invention are particularly active againstbacteria and bacterialike microorganisms. They are thereforeparticularly suitable for the prophylaxis and chemotherapy of local andsystemic infections in human and veterinary medicine that are induced bythese pathogens.

By way of example it is possible to treat and/or prevent local and/orsystemic diseases caused by the following pathogens or by combinationsof the following pathogens:

Gram-positive cocci, e.g., staphylococci (Staph. aureus, Staph.epidermidis), enterococci (E. faecalis, E. faecius) and streptococci(Strept. agalactiae, Strept. pneumoniae); gram-negative cocci (Neisseriagonorrhoeae) and gram-negative rods such as enterobacteria, e.g.,Escherichia coli, hemophilus influenzae, Citrobacter (Citrob. freundii,Citrob. divernis), salmonella and shigella; and also Klebsiellas (Klebs.pneumoniae, Klebs. oxytocy), Enterobacter (Ent. aerogenes, Ent.agglomerans), hafnia, serratia (Serr. marcescens), providencia,yersinia, and also the genus Acinetobacter. The antibacterial spectrumfurther embraces strictly anaerobic bacteria such as Bacteroidesfragilis, representatives of the genus Peptococcus, Peptostreptococcusand the genus Clostridium; and also Mycoplasmas (M. pneumoniae, M.hominis, M. urealyticum) and Mycobacteria, e.g., Mycobacteriumtuberculosis.

The above listing of pathogens should be interpreted merely as exemplaryand in no way as restrictive. Examples that may be mentioned of diseaseswhich may be caused by the stated pathogens or combination infectionsand which may be prevented, remedied or cured by the formulations of theinvention include the following:

Infectious diseases in humans, such as septic infections, bone and jointinfections, skin infections, postoperative wound infections, abscesses,phlegmons, wound infections, infected burns, burn wounds, infections inthe oral region, infections following dental operations, septicarthritis, mastitis, tonsillitis, genital infections and eye infections.

As well as in humans, bacterial infections in other species too can betreated. Examples that may be mentioned include the following:

pigs: coli diarrhea, enterotoxemia, sepsis, dysenteria, salmonellosis,metritis-mastitis-agalactia syndrome, mastitis;ruminants (cattle, sheep, goats): diarrhea, sepsis, bronchopneumonia,salmonellosis, pasteurellosis, mycoplasmosis, genital infections;horses: bronchopneumonias, joint ill, puerperal and postpartuminfections, salmonellosis;dogs and cats: bronchopneumonia, diarrhea, dermatitis, otitis, urinarytract infections, prostatitis;poultry (chickens, turkeys, quails, pigeons, ornamental birds andothers): mycoplasmosis, E. coli infections, chronic respiratory tractdiseases, salmonellosis, pasteurellosis, psittacosis.

It is also possible to treat bacterial diseases associated with thebreeding and keeping of farmed and ornamental fish, in which case theantibacterial spectrum extends beyond the aforementioned pathogens toembrace further pathogens such as Pasteurella, Brucella, Campylobacter,Listeria, Erysipelothris, Corynebacteria, Borellia, Treponema, Nocardia,Rickettsi, Yersinia, for example.

The active ingredient may act systemically and/or locally. For thatpurpose it can be administered in appropriate manner, such as orally,parenterally, pulmonically, nasally, sublingually, lingually, buccally,rectally, transdermally, conjunctivally, otically or as an implant.

For these administration routes the active ingredient can beadministered in suitable administration forms.

Administration forms suitable for oral administration are known suchforms which deliver the active ingredient rapidly and/or in a modifiedway, such as tablets (uncoated and coated tablets, such as film-coatedtablets or tablets provided with enteric coatings), capsules,sugar-coated tablets, granules, pellets, powders, emulsions, suspensionsand solutions.

Parenteral administration can be made with avoidance of an absorptionstep (intravenously, intraarterially, intracardially, intraspinally orintralumbarly) or wity inclusion of absorption (intramuscularly,subcutaneously, intracutaneously, percutaneously, or intraperitoneally).Administration forms suitable for parenteral administration includepreparations for injection and infusion in the form of solutions,suspensions, emulsions, lyophilisates and sterile powders.

Preference is given to parenteral administration, more particularlyintravenous administration.

Examples suitable for the other administration routes are pharmaceuticalforms for inhalation (including powder inhalers, nebulizers), nasaldrops/solutions, sprays; capsules or tablets to be administeredlingually, sublingually or buccally, suppositories, ear and eyepreparations, vaginal capsules, aqueous suspensions (lotions,shaking-mixtures), lipophilic suspensions, ointments, creams, milk,pastes, dusting powders or implants.

The active ingredients can be converted in conventional manner into thestated administration forms. This is done with the use of inert,nontoxic, pharmaceutically appropriate auxiliaries (excipients). Theseinclude, among others, carriers (e.g., microcrystalline cellulose),solvents (e.g. liquid polyethylene glycols), emulsifiers (e.g., sodiumdodecyl sulfate), dispersants (e.g., polyvinylpyrrolidone), syntheticand natural biopolymers (e.g., albumen), stabilizers (e.g., antioxidantssuch as ascorbic acid), colorants (e.g., inorganic pigments such as ironoxides) or flavor and/or odor masking agents.

It has generally proven advantageous in the case of parenteraladministration to administer amounts of about 5 to 250 mg/kg body weightper 24 hours in order to achieve effective results. In the case of oraladministration the amount is about 5 to 100 mg/kg body weight per 24hours.

It may nevertheless be necessary, where appropriate, to deviate from theamounts specified, specifically as a function of body weight,administration route, individual response to the active ingredient, typeof formulation, and time or interval at which administration takesplace.

The percentages in the tests and examples below, unless statedotherwise, are percentages by weight; parts are parts by weight. Solventratios, dilution ratios and concentration figures for liquid/liquidsolutions are based in each case on the volume.

A. EXAMPLES

Reaction schemes which are shown for general procedures show a selectionof examples, but can be employed in each case for all of the exampleswhich refer to them.

ABBREVIATIONS

-   Boc tert-butoxycarbonyl-   CDCl₃ deuterochloroform-   DCI direct chemical ionization-   DIEA N,N-diisopropylethylamine-   DMSO dimethyl sulfoxide-   EDC N-(3-dimethylaminoisopropyl)-N′-ethylcarbodiimide hydrochloride-   eq. equivalent-   ESI electrospray ionization (for MS)-   Fmoc fluorenylmethoxycarbonyl-   h hour-   HATU O-(7-azabenzotriazol-1-yl)-N,N,N′-tetramethyluronium    hexafluorophosphate-   HOBt 1-hydroxylbenzotriazole-   HPLC High-pressure, high-performance liquid chromatography-   LC-MS liquid chromatography-coupled mass spectroscopy-   MS mass spectroscopy-   NMR nuclear magnetic resonance spectroscopy-   PS-DIEA N,N-diisopropylethylamine-polystyrene (Resin)-   R_(f) retention index (for TLC)-   RP-HPLC reverse phase HPLC-   RT room temperature-   R_(t) retention time (for HPLC)-   THF tetrahydrofuran

HPLC and LC-MS Methods:

Method 1: column: Kromasil C18, L-R temperature: 30° C., flow rate=0.75ml min⁻¹, mobile phase: A=0.01 M HClO₄, B=acetonitrile, gradient:→ 0.5min 98% A →4.5 min 10% A →6.5 min 10% A

Method 2: column: Kromasil C18 60*2, L-R temperature: 30° C., flowrate=0.75 ml min⁻¹, mobile phase: A=0.01 M H₃PO₄, B=acetonitrile,gradient: δ 0.5 min 90% A→4.5 min 10% A→6.5 min 10% A

Method 3: column: Kromasil C18 60*2, L-R temperature: 30° C., flowrate=0.75 ml min⁻¹, mobile phase: A=0.005 M HClO₄, B=acetonitrile,gradient: δ 0.5 min 98% A→4.5 min 10% A→6.5 min 10% A

Method 4: column: Symmetry C18 2.1×150 mm, column oven: 50° C., flowrate=0.6 ml min⁻¹, mobile phase: A=0.6 g 30% strength hydrochloricacid/1 water, B=acetonitrile, gradient: 0.0 min 90% A→4.0 min 10% A→9min 10% A

Method 5: Instrument: Micromass Quattro LCZ

Column: Symmetry C18, 50 mm×2.1 mm, 3.5 μm, temperature: 40° C., flowrate=0.5 ml min⁻¹, mobile phase A=acetonitrile+0.1% formic acid, mobilephase B=water+0.1% formic acid, gradient: 0.0 min 10% A→4 min 90% A→6min 90% A

Method 6: Instrument: Micromass Platform LCZ

Column: Symmetry C18, 50 mm×2.1 mm, 3.5 μm, temperature: 40° C., flowrate=0.5 ml min⁻¹, mobile phase A=acetonitrile+0.1% formic acid, mobilephase B=water+0.1% formic acid, gradient: 0.0 min 10% A→4 min 90% A→6min 90% A

Method 7: Instrument: Micromass Quattro LCZ

Column: Symmetry C18, 50 mm×2.1 mm, 3.5 μm, temperature: 40° C., flowrate=0.5 ml min⁻¹, mobile phase A=acetonitrile+0.1% formic acid, mobilephase B=water+0.1% formic acid, gradient: 0.0 min 5% A→1 min 5% A→5 min90% A→6 min 90% A

Method 8: column: Symmetry C18 2.1×150 mm, 5 μm, column oven: 70° C.,flow rate=0.9 ml min⁻¹, mobile phase: A=acetonitrile, B=0.3 g 30%strength hydrochloric acid/1 water, gradient: 0.0 min 2% A→2.5 min 95%A→5 min 95% A

Method 9: column: Symmetry C18 3.9×150 mm, column oven: 40° C., flowrate=1.5 ml min⁻¹, mobile phase: A=water+0.05% H₃PO₄, B=acetonitrile,gradient: 0.0 min 10% B→0.6 min 10% B→3.8 min 100% B→5.0 min 100% B.

Method 10: Instrument: Waters Alliance 2790 LC; column: Symmetry C18, 50mm×2.1 mm, 3.5 μm; mobile phase A: water+0.1% formic acid, mobile phaseB: acetonitrile+0.1% formic acid; gradient: 0.0 min 5% B→5.0 min 10%B→6.0 min 10% B; temperature: 50° C., flow rate: 1.0 ml/min, UVdetection: 210 nm.

Method 11: Instrument type MS: Micromass ZQ; instrument type HPLC:Waters Alliance 2790; column: Symmetry C18, 50 mm×2.1 mm, 3.5 μm; mobilephase B: acetonitrile+0.05% formic acid, mobile phase A: water+0.05%formic acid; gradient: 0.0 min 10% B→3.5 min 90% B→5.5 min 90% B; oven:50° C., flow rate: 0.8 ml/min, UV detection: 210 nm.

Method 12: Instrument: Waters Alliance 2790 LC; column: Symmetry C18, 50mm×2.1 mm, 3.5 μm; mobile phase A: water+0.05% formic acid, mobile phaseB: acetonitrile+−0.05% formic acid; gradient: 0.0 min 5% B→4.5 min 10%B→5.5 min 10% B; temperature: 50° C., flow rate: 1.0 ml/min, Ldetection: 210 nm.

Method 13: Instrument: Micromass Quattro LCZ, HP1100; column: SymmetryC18, 50 mm×2.1 mm, 3.5 μm; mobile phase A: water+0.05% formic acid,mobile phase B: acetonitrile+0.05% formic acid; gradient: 0.0 min 90%A→4.0 min 10% A→6.0 min 10% A; Oven: 40° C., flow rate: 0.5 ml/min, UVdetection: 208-400 nm.

Method 14: Instrument: Micromass Platform LCZ, HP1100; column: SymmetryC18, 50 mm×2.1 mm, 3.5 μm; mobile phase A: water+0.05% formic acid,mobile phase B: acetonitrile+0.05% formic acid; gradient: 0.0 min 90%A→4.0 min 10% A→6.0 min 10% A; oven: 40° C., flow rate: 0.5 ml/min, UVdetection: 208-400 mm.

Method 15: Instrument: Waters Alliance 2790 LC; column: Symmetry C18, 50mm×2.1 mm, 3.5 μm; mobile phase A: water+0.05% formic acid, mobile phaseB: acetonitrile+0.05% formic acid; gradient: 0.0 min 10% B→4.0 min 90%B→6.0 min 90% B; temperature: 50° C., flow rate: 0.0 min 0.5 ml/min→4.0min 0.8 ml/min, UV detection: 210 nm.

Method 16: Instrument type MS: Micromass ZQ; instrument type HPLC:Waters Alliance 2790; column: Symmetry C18, 50 mm×2.1 mm, 3.5 μm; mobilephase B: acetonitrile+0.05% formic acid, mobile phase A: water+0.05%formic acid; gradient: 0.0 min 5% B 4.5 min 90% B 5.5 min 90% B; oven:50° C., flow rate: 1.0 ml/, UV detection: 210 nm

Method 17: Instrument type MS: Micromass ZQ; instrument type HPLC:Waters Alliance 2790; column: Uptisphere C18, 50 mm×2.0 mm, 3.0 μm;mobile phase B: acetonitrile+0.05% formic acid, mobile phase A:water+0.05% formic acid; gradient: 0.0 min 5% B→2.0 min 40% B→4.5 min90% B→5.5 min 90% B; oven: 45° C., flow rate: 0.0 min 0.75 ml/min→4.5min 0.75 ml/min→5.5 min 1.25 ml/min, UV detection: 210 nm

Method 18: Instrument: Micromass Platform LCZ with HPLC Agilent series1100; column: Grom-SIL120 ODS-4 HE, 50 mm×2.0 mm, 3 μm; mobile phase A:1 l water+1 ml 50% strength formic acid, mobile phase B: 1 lacetonitrile+1 ml 50% strength formic acid; gradient: 0.0 min 100% A→0.2min 100% A→2.9 min 30% A→3.1 min 10% A→4.5 min 10% A; oven: 55° C., flowrate: 0.8 ml/min, UV detection: 208-400 nm.

Method 19: Instrument: Micromass Quattro LCZ, with HPLC Agilent series1100; column: Grom-SIL120 ODS-4 HE, 50 mm×2.0 mm, 3 μm; mobile phase A:1 l water+1 ml 50% strength formic acid, mobile phase B: 1 lacetonitrile+1 ml 50% strength formic acid; gradient: 0.0 min 100% A→0.2min 100% A→2.9 min 30% A→3.1 min 10% A→4.5 min 10% A; oven: 55° C., flowrate: 0.8 min, UV detection: 208-400 nm.

Method 20: Instrument type MS: Micromass ZQ; instrument type HPLC:Waters Alliance 2790; column: Grom-Sil 120 ODS-4 HE 50×2 mm, 3.0 μm;mobile phase B: acetonitrile+0.05% formic acid, mobile phase A:water+0.05% formic acid; gradient: 0.0 min 5% B→2.0 min 40% B→4.5 min90% B→5.5 min 90% B; oven: 45° C.; flow rate: 0.0 min 0.75 ml/min→4.5min 0.75 ml/min→5.5 min 1.25 ml/min; UV detection: 210 nm.

Method 21: Instrument type MS: Micromass ZQ; instrument type HPLC:Waters Alliance 2790; column: Grom-Sil 120 ODS-4 HE 50×2 mm, 3.0 μm;mobile phase B: acetonitrile+500 ul 50% strength formic acid/1; mobilephase A: water+500 ul 50% strength formic acid/1; gradient: 0.0 min 0%B→0.2 min 0% B→2.9 min 70% B→3.1 min 90% B→4.5 min 90% B, oven: 50° C.,flow rate:0.8 ml/min; UV detection: 210 nm.

Method 22: Instrument: Micromass Quattro LCZ with HPLC Agilent series1100; column: UPTISPHERE HDO, 50 mm×2.0 mm, 3 μm; mobile phase A: 1 lwater+1 ml 50% strength formic acid, mobile phase B: 1 l acetonitrile+1ml 50% strength formic acid; gradient: 0.0 min 100% A→0.2 min 100% A→2.9min 30% A→3.1 min 10% A→4.5 min 10% A; oven: 55° C., flow rate: 0.8m/min, UV detection: 208-400 nm.

Starting Compounds: Example 1A (3S)-1,3-Dimethyl-2,5-pyrrolidinedione

600 mg (5.26 mmol) of (3S)-3-methyldihydro-2,5-furandione (preparation:S. G. Davies, D. J. Dixon, J. Chem. Soc., Perkin Trans. 1, 1998, 17,2635-2643) are introduced to a vessel together with 559 mg (0.77 ml,5.52 mmol) of triethylamine in 5 ml of dichloromethane at 0° C. and 373mg (5.52 mmol) of methylamine hydrochloride are added. The reactionmixture is stirred at room temperature overnight and then 938 mg (5.78mmol) of N,N-carbonyldiimidazole are added in portions. The mixture isstirred at room temperature for 1.5 h and at reflux temperature for 30minutes. After it has cooled to room temperature the reaction mixture iswashed with 5% strength hydrochloric acid and water, the organic phaseis dried over magnesium sulfate, filtered and concentrated and theproduct is dried under a high vacuum. This gives 605 mg of the product(88% of theory).

MS (ESI+): m/z (%)=128 (M+H⁺) (100).

HPLC (method 6): R_(t)=0.81 min.

¹H-NMR (300 MHz, CDCl₃): δ=3.10 (dd, 1H), 2.99 (s, 3H), 2.90-2.82 (m,1H), 2.32 (dd, 1H), 1.35 (d, 3H).

Example 2A(3R,4S)-3-[(2S)-2-(tert-Butoxycarbonyl)amino-3-methylbutanoyl]-1,4-dimethyl-2,5-pyrrolidinedione

684 mg (3.15 mmol) of N-(tert-butoxycarbonyl)-L-valine and 561 mg (3.46mmol) of N,N-carbonyldiimidazole are stirred in 4 ml of tetrahydrofuranat room temperature for 2 h. Then 400 mg (3.15 mmol) of(3S)-3-1,3-dimethyl-2,5-pyrrolidinedione are added to this mixture andthe whole mixture is added dropwise over the course of 30 minutes to 6.3ml of a 1 molar solution of lithium hexamethyldisilazide in THF, whichhas been cooled to −65° C. After the end of the addition stirring iscontinued at −65° C. for 15 minutes more, and then 6 ml of saturatedaqueous ammonium chloride are added. After the reaction mixture has beenwarmed to room temperature it is diluted with diethyl ether and theorganic phase is washed with saturated aqueous sodium chloride solutionand subsequently concentrated. The crude product is purified by RP-HPLC(mobile phase: water-acetonitrile, gradient). This gives 223 mg (22% oftheory) of the desired product.

MS (ESI−): m/z (%)=325 (M−H⁺) (35).

HPLC (method 5): R_(t)=3.99 min.

¹H-NMR (200 MHz, CDCl₃): δ=5.70 (br. d, 1H), 4.57 (dd, 1H), 3.78 (d,1H), 3.47-3.30 (m, 1H), 2.98 (s, 3H), 2.50-2.32 (m, 1H), 1.46 (s, 9H),1.32 (d, 3H), 1.02 (d, 3H), 0.80 (d, 3H).

In the same way as for Example 2A it is possible by reacting thecorresponding N-tert-butoxycarbonyl-protected amino acids with(3S)-1-(benzyloxy)-3-methyl-2,5-pyrrolidinedione preparation: S. G.Davies, D. J. Dixon, J. Chem. Soc., Perkin Trans. 1, 1998, 17,2635-2643) to prepare the following derivatives (Examples 3A to 5A):

Example 3A(3R,4S)-1-Benzyloxy-3-[(2S)-2-(tert-butoxycarbonyl)amino-3,3-dimethylbutanoyl]-4-methyl-2,5-pyrrolidinedione

MS (ESI−): m/z (%)=431 (M−H⁺) (100).

HPLC (method 6): R_(t)=4.87 min.

Example 4A(3R,4S)-1-Benzyloxy-3-[(2S)-2-(tert-butoxycarbonyl)amino-4-methylpentanoyl]-4-methyl-2,5-pyirolidinedione

MS (ESI−): m/z (%)=431 (M−H⁺) (100).

HPLC (method 6): R_(t)=4.88 min.

Example 5A(3R,4S)-1-Benzyloxy-3-[(2S)-2-(tert-butoxycarbonyl)amino-butanoyl]-4-methyl-2,5-pyrrolidinedione

MS (ESI−): m/z (%)=403 (M−H⁺) (100).

HPLC (method 6): R_(t)=4.54 min.

General Instructions A: Reductive Deprotection of1-benzyloxy-2,5-pyrrolidinediones

Deprotection takes place in a manner similar to that of S. G. Davies, D.J. Dixon, J. Chem. Soc., Perkin Trans. 1 1998, 2635-2643.

The 1-benzyloxy-2,5-pyrrolidinedione (1 eq.) is dissolved in methanol orethanol (about 0.02 mol/l), a catalytic amount of palladium-on-carbon(10%) is added, and the mixture is stirred under a hydrogen atmosphere(atmospheric pressure) for 1 h. The reaction mixture is then filteredand concentrated. The residue is dissolved in acetonitrile (about 0.05mol/l) and added dropwise at room temperature to a solution of2-bromoacetophenone (1 eq) in acetonitrile (about 0.03 mol/l) at roomtemperature. Thereafter over a period of 2 h, 1.5 eq. of triethylaminein acetonitrile (about 0.35 mol/l) are added dropwise to the reactionmixture. The reaction mixture is stirred at room temperature overnightand concentrated and the crude product is purified by means of RP-HPLC(mobile phase: acetonitrile/water or acetonitrile/water+0.3 ml 37%strength hydrochloric acid/l, gradient).

Example 6A(3R,4S)-3-[(2S)-2-(tert-Butoxycarbonyl)amino-3,3-dimethylbutanoyl]-4-methyl-2,5-pyrrolidinedione

Preparation is in accordance with general instructions A.

MS (ESI+): m/z (%)=327 (M+H⁺) (100).

HPLC (method 5): R_(t)=3.87 min.

Example 7A(3R,4S)-3-[(2S)-2-(tert-Butoxycarbonyl)amino-4-methylpentanoyl]-4-methyl-2,5-pyrrolidinedione

Preparation is in accordance with general instructions A.

MS (ESI−): m/z (%)=325 (M−H⁺) (100).

HPLC (method 5): R_(t)=3.91 min.

Example 8A(3R-4S)-3-[(2S)-2-(tert-Butoxycarbonyl)amino-butanoyl]-4-methyl-2,5-pyrrolidinedione

Preparation is in accordance with general instructions A.

MS (ESI−): m/z (%)=297 (M−H⁺) (100).

HPLC (method 6): R_(t)=3.50 min.

Example 9A(3R,4S)-3-[(2S)-2-Amino-3-methylbutanoyl]-4-methyl-2,5-pyrrolidinedionehydrochloride

A solution, cooled at 0° C., of 4.40 g (14.09 mmol) of(3R,4S)-3-[(2S)-2-(tert-butoxycarbonyl)amino-3-methylbutanoyl]-4-methyl-2,5-pyrrolidinedione(preparation: S. G. Davies, D. J. Dixon, J. Chem. Soc., Perkin Trans. 1,1998, 17, 2635-2643) is admixed dropwise with 35 ml of 4N hydrochloricacid solution in 1,4-dioxane. When the addition is at an end the mixtureis warmed to room temperature and stirred for 2 h, after which themixture is concentrated under reduced pressure. The crude product can beused directly in the next stage. If desired the residue is treated withdiethyl ether and the crystals precipitated are filtered off and driedunder a high vacuum. Yield: 2.99 g of colorless crystals (86% oftheory).

MS (ESI+): m/z (%)=213 (M+H⁺) (100).

HPLC (method 4): R_(t)=0.41 min.

In the same way as for Example 9A it is possible, from the correspondingtert-butoxycarbonylamino derivatives, by treatment with hydrochloricacid/dioxane, to prepare the following amines (Examples 10A to 13A) inthe form of their hydrochlorides:

Example 10A(3R,4S)-3-[(2S)-2-Amino-3-methylbutanoyl]-1,4-dimethyl-2,5-pyrrolidinedionehydrochloride

MS (ESI+): m/z (%)=227 (M+H⁺) (80).

Example 11A(3R,4S-3-[(2S)-2-Amino-3,3-dimethylbutanoyl]-4-methyl-2,5-pyrrolidinedionehydrochloride

MS (ESI+): m/z (%)=227 (M+H⁺) (100).

Example 12A(3R,4S)-3-[(2S)-2-Amino-4-methylpentanoyl]-4-methyl-2,5-pyrrolidinedionehydrochloride

MS (ESI+): m/z (%)=227 (M+H⁺) (100).

Example 13A(3R,4S)-3-[(2S)-2-Amino-butanoyl]-4-methyl-2,5-pyrrolidinedionehydrochloride

MS (ESI+): m/z (%)=199 (M+H⁺) (100).

General Instructions B: Reaction of 3-Aminopropionic Acid Alkyl Esterswith Carboxylic Acids

A solution of the carboxylic acid derivative (1.2-1.5 eq.) in absolutedichloromethane or a mixture (5:1 to 1:1) of absolute dichloromethaneand N,N-dimethylformamide (about 0.1 to 0.3 mol/l) is admixed at 0° C.first with an equimolar amount of HATU and then with the3-aminopropionic acid alkyl ester (1 eq., optionally as a solution inN,N-dimethylfomamide or dichloromethane/N,N-dimethylformamide mixtures).Subsequently at 0° C. a solution of 2.5-3.5 eq. of diisopropylethylaminein a 1:1 mixture of absolute dichloromethane and N,N-dimethylformamide(0.2-1 mol/l) is added dropwise over a period of 1 h. When the additionis at an end the reaction mixture is stirred at 0° C. for 30 minutesmore and then at room temperature overnight, before being concentratedunder reduced pressure. The product can be obtained by chromatography onsilica gel (mobile phases: mixtures of cyclohexane/ethyl acetate ormixtures of dichloromethane and ethanol) or by RP-HPLC (mobile phases:variable gradients of water and acetonitrile), or alternatively by acombination of both methods.

((S)-3-Amino-3-phenylpropionic acid methyl ester, preparation: S. G.Davies et. al., J. Chem. Soc., Chem. Comm., 1993, 14, 1153-1155).

Alternatively the reaction can take place by the following method aswell:

A solution of the 3-aminopropionic acid alkyl ester (1 eq.) in absolutedichloromethane or a mixture (5:1 to 1:1) of absolute dichloromethaneand N,N-dimethylformamide (about 0.1 to 0.3 mol/l) is admixed with thecarboxylic acid derivative (1.1-1.5 eq.), triethylamine (3 eq.), HOBt (3eq.) and finally 1.2 eq. of EDC. The reaction mixture is stirred at roomtemperature (2 h to overnight), before being concentrated under reducedpressure. The residue is taken up in ethyl acetate or dichloromethaneand the organic phase is washed with water, saturated sodiumhydrogencarbonate solution and saturated sodium chloride solution, driedover sodium sulfate, filtered and concentrated. The product can bepurified by chromatography on silica gel (mobile phases: mixtures ofcyclohexane/ethyl acetate or mixtures of dichloromethane and ethanol) orby RP-HPLC (mobile phases: variable gradients of water andacetonitrile), or alternatively by a combination of both methods.

Example 14A Methyl(3S)-3-{[(2E)-3-(1,3-benzodioxol-5-yl)-2-propenoyl]amino}-3-phenylpropionate

Preparation takes place in accordance with general instructions B.

¹H-NMR (300 MHz, d₆-DMSO): δ=8.50 (d, 1H), 7.38-7.21 (m, 6H), 7.14 (d,1H), 7.06 (dd, 1H), 6.93 (d, 1H), 6.49 (d, 1H), 6.05 (s, 2H), 5.32 (q,1H), 3.56 (s, 3H), 2.91-2.78 (m, 2H).

MS (ESI+): m/z (%)=354 (M+H⁺) (65).

General Instructions C: Hydrolysis of the Propionic Acid Alkyl Esters

The propionic acid alkyl ester is introduced to a vessel in a 3:1mixture of ethanol and water (about 0.1-0.15 mol/l) and 5 eq. of 40%strength sodium hydroxide solution are added. The reaction mixture isstirred at room temperature for 24 h, acidified with dilute hydrochloricacid (to a pH of about 3) and concentrated. The residue is taken up inethyl acetate and washed with saturated aqueous sodium chloridesolution. The organic phase is dried over magnesium sulfate, filteredand concentrated. The product obtained can be used without furtherpurification in the next stage.

An alternative option is to use the following method:

The propionic acid alkyl ester is introduced to a vessel in a 1:1mixture of dioxane and water (about 0.1-0.15 mol/l) and 3 eq. of asolution of potassium hydroxide in methanol (100 mg/ml) are added. Thereaction mixture is stirred at room temperature for 2 h and thenconcentrated. The residue is taken up in water and acidified with dilutehydrochloric acid. The aqueous phase is extracted three times with a 1:1mixture of dichloromethane and ethyl acetate. The combined organicphases are dried over sodium sulfate, filtered and concentrated. Theproduct obtained can be used without further purification in the nextstage.

Example 15A(3S)-3-{[(2E)-3-(1,3-Benzodioxol-5-yl)-2-propenoyl]amino}-3-phenylpropionicAcid

Preparation takes place in accordance with general instructions C.

¹H-NMR (300 MHz, d₆-DMSO): δ=12.21 (s, 1H), 8.50 (d, 1H), 7.38-7.21 (m,6 H), 7.14 (d, 1H), 7.06 (dd, 1H), 6.93 (d, 1H), 6.50 (d, 1H), 6.06 (s,2H), 5.31 (q, 1H), 2.83-2.66 (m, 2H).

MS (ESI+): m/z (%)=340 (M+H⁺) (85).

HPLC (method 5): R_(t)=3.47 min.

The propionic acid derivatives obtained in this way can be reacted inaccordance with general instructions D (acylation of3-[2-aminoalkanoyl]-2,5-pyrrolidinedione hydrochloride derivatives withcarboxylic acid derivatives).

General Instructions D: Acylation of3-[2-aminoalkanoyl]-2,5-pyrrolidinedione Hydrochloride Derivatives withCarboxylic Acid Derivatives

A solution of carboxylic acid derivative (1.2-1.5 eq.) in absolutedichloromethane or a mixture (5:1 to 1:1) of absolute dichloromethaneand N,N-dimethylformamide (about 0.1 to 0.3 mol/l) is admixed at 0° C.first with an equimolar amount of HATU and then with the3-[2-aminoalkanoyl]-2,5-pyrrolidinedione hydrochloride derivative (1eq., optionally as a solution in N,N-dimethylformamide ordichloromethane/N,N-dimethylformamide mixtures). Subsequently at 0° C. asolution of 2.5-3.5 eq. of diisopropylethylamine in a 1:1 mixture ofabsolute dichloromethane and N,N-dimethylformamide (0.2-1 mol/l) isadded dropwise over a period of 1 h. After the end of the addition thereaction mixture is stirred at 0° C. for 30 minutes more and then atroom temperature overnight, before being concentrated under reducedpressure. The product can be obtained by chromatography on silica gel(mobile phases: mixtures of cyclohexane/ethyl acetate or mixtures ofdichloromethane and ethanol) or by RP-HPLC (mobile phases: variablegradients of water and acetonitrile), or alternatively by a combinationof both methods.

Alternatively the reaction may also take place by the following method:

A solution of the 3-[2-aminoalkanoyl]-2,5-pyrrolidinedione hydrochloridederivative (1 eq.) in absolute dichloromethane or a mixture (5:1 to 1:1)of absolute dichloromethane and N,N-dimethylformamide (about 0.1 to 0.3mol/l) is admixed with the carboxylic acid derivative (1.1-1.5 eq.),triethylamine (3 eq.), HOBt (3 eq.) and finally 1.2 eq. of EDC. Thereaction mixture is stirred at room temperature (2 h to overnight)before being concentrated under reduced pressure. The residue is takenup in ethyl acetate or dichloromethane and the organic phase is washedwith water, saturated sodium hydrogencarbonate solution and saturatedsodium chloride solution, dried over sodium sulfate, filtered andconcentrated. The product can be purified by chromatography on silicagel (mobile phases: mixtures of cyclohexane/ethyl acetate or mixtures ofdichloromethane and ethanol) or by RP-HPLC (mobile phases: variablegradients of water and acetonitrile), or alternatively by a combinationof both methods.

Example 16A tert-Butyl((S)-2-{(S)-2-methyl-1-[1-((3R,4S)-4-methyl-2,5-dioxo-pyrrolidin-3-yl)-methanoyl]-propylcarbamoyl}-1-phenylethyl)carbamate

Preparation is in accordance with general instructions D.

¹H-NMR (400 MHz, d₆-DMSO): δ=11.45 (s, 1H), 7.98 (d, 1H), 7.31-7.24 (m,5H), 7.20 (br. s, 1H), 4.88-4.82 (br. s, 1H), 4.69 (br. s, 1H), 3.98 (d,1H), 2.95-2.89 (m, 1H), 2.77-2.69 (m, 1H), 2.51-2.44 (m, 1H), 2.35-2.29(m, 1H), 1.10 (d, 3H), 0.85 (d, 3H), 0.78 (d, 3H).

MS (ESI+): m/z (%)=460 (M+H⁺) (100).

HPLC (method 6): R_(t)=3.90 min.

General Instructions E: Deblocking of Boc-Protected Derivatives

The tert-butyloxycarbonyl (BOC) protected amine derivative (optionallyas a solution in dioxane) is admixed at 0° C. or room temperature with4N hydrochloric acid solution in 1,4-dioxane (about 0.1 mol/l) andstirred at room temperature for 2 to 24 h before being concentratedunder reduced pressure. The residue can be reacted further withoutadditional purification or if desired is desired is treated withdichloromethane and diethyl ether (about 1:2). The precipitated crystalsare filtered off with suction and dried under a high vacuum. This givesthe product as the hydrochloride.

Example 17A(S)-3-Amino-{(S)-2-methyl-1-[1-((3R,4S)-4-methyl-2,5-dioxopyrrolidin-3-yl)-methanoyl]-propyl}-3-phenylpropionamideHydrochloride

Preparation takes place in accordance with general instructions E.

¹H-NMR (200 MHz, d₆-DMSO): δ=11.49 (br. s, 1H), 8.5 (br. s, about 3H),7.54-7.32 (m, 5H), 4.69-4.55 (m, 2H), 3.89 (d, 1H), 3.06-2.80 (m, 3H),2.39-2.25 (m, 1H), 1.01 (d, 3H), 0.81 (d, 3H), 0.75 (d, 3H).

MS (ESI+): m/z (%)=360 (M−Cl)⁺ (100).

HPLC (method 4): R_(t)=1.44 min.

Example 18A Methyl3-amino-3-(2,3-dihydro-1,4-benzodioxin-6-yl)propionate

3-Amino-3-(2,3-dihydro-1,4-benzodioxin-6-yl)propionic acid [synthesisaccording to instructions known from the literature (e.g., L. Lázár, T.Martinek, G. Bernáth, F. Fülöp, Synth. Comm. 1998, 28, 219-224)] isintroduced into a vessel in methanol (about 0.5 to 1.0 mol/l) andadmixed dropwise at 0° C. with 1.2 eq of thionyl chloride. When theaddition has been made the reaction mixture is stirred at roomtemperature overnight and subsequently concentrated. The residue isdissolved in a little methanol and the product is precipitated withdiethyl ether. The solid is filtered off with suction, washed repeatedlywith diethyl ether and dried under reduced pressure.

¹H-NMR (300 MHz, d₆-DMSO): δ=8.51 (br. s, 3H), 7.07 (d, 1H), 6.95 (dd,1H), 6.88 (d, 1H), 4.48 (dd, 1H), 4.24 (s, 4H), 3.57 (s, 3H), 3.12 (dd,1H), 2.94 (dd, 1H).

MS (ESI+): m/z=238 (M+H⁺).

In the same way as for Example 1A the following compounds (Example 19Ato 26A) can be obtained by reacting (3S)-3-methyldihydro-2,5-furandionewith the corresponding primary amines, hydroxylamine derivatives orhydrazine derivatives. The crude products can be purified by RP-HPLC(mobile phase: water-acetonitrile, gradient).

Example Structure MW MS HPLC 19A

219.24 HPLC (method 6): R_(t) = 3.37 min 20A

156.18 MS (ESI+), m/z: 157 (M + H)⁺ HPLC (method 19): R_(t) = 2.62 min21A

157.17 MS (DCI), m/z: 175 (M + NH₄)⁺ HPLC (method 20): R_(t) = 1.70 min22A

228.25 MS (DCI), m/z: 246 (M + NH₄)⁺ HPLC (method 20): R_(t) = 2.09 min23A

143.14 MS (ESI+), m/z: 144 (M + H)⁺ 24A

276.29 MS (DCI), m/z: 294 (M + NH₄)⁺ HPLC (method 21): R_(t) = 2.80 min25A

155.20 MS (ESI+), m/z: 156 (M + H)⁺ HPLC (method 19): R_(t) = 3.26 min26A

141.17 MS (ESI+), m/z: 142 (M + H)⁺ HPLC (method 19): R_(t) = 2.78 min

General Instructions F: Reaction of N-tert-butoxycarbonyl-ProtectedAmino Acids with 2,5-pyrrolidinedione Derivatives

The N-tert-butoxycarbonyl-protected amino acid (1 eq.) andN,N-carbonyldiimidazole (1.1 eq.) are stirred in tetrahydrofuran (about0.1-1 mol/l) at room temperature for 2 h. The 2,5-pyrrolidinedione (1eq.) is then added to this mixture and the total mixture is addeddropwise over the course of 30 minutes to a 1 molar solution of lithiumhexamethyldisilazide (2 eq.) in THF, which is cooled at −65° C. Afterthe end of the addition stirring is continued at −65° C. for 15 minutesmore, and then saturated aqueous ammonium chloride solution is added.After the reaction mixture has been warmed to room temperature it isdiluted with diethyl ether and the organic phase is washed withsaturated aqueous sodium chloride solution, dried over magnesiumsulfate, filtered and subsequently concentrated. The crude product ispurified by RP-HPLC (mobile phase: water-acetonitrile, gradient).

In accordance with general instructions F it is possible by reacting thecorresponding N-tert-butoxycarbonyl-protected amino acids (for thepreparation of non-natural alpha-amino acids see, for example, A. A.Cordi et al., J. Med. Chem. 2001, 44, 787-805; K. Mai, G. Patil,Tetrahedron Lett. 1984, 25, 4583-4586; N. A. Hassan, E. Bayer, J. C.Jochims, J. Chem. Soc., Perkin Trans. 1 1998, 3747-3757; for thetert-butoxycarbonyl protection see, e.g., T. W. Greene, P. G. M. Wuts,Protective Groups in Organic Synthesis, 3^(rd) Edt. 1999, J. Wiley &Sons, Inc.) with 2,5-pyrrolidinediones to obtain the followingderivatives (Examples 27A to 52A):

Example Structure MW MS HPLC 27A

432.51 MS (ESI−), m/z: 431 (M − H)⁻ HPLC (method 10): R_(t) = 4.10 min28A

458.55 MS (ESI−), m/z: 457 (M − H)⁻ HPLC (method 12): R_(t) = 4.12 min29A

444.53 MS (ESI−), m/z: 443 (M − H)⁻ HPLC (method 18): R_(t) = 4.11 min30A

432.51 MS (ESI−), m/z: 431 (M − H)⁻ HPLC (method 6): R_(t) = 4.88 min31A

432.51 MS (ESI−), m/z: 431 (M − H)⁻ HPLC (method 13): R_(t) = 5.08 min32A

432.51 MS (ESI−), m/z: 431 (M − H)⁻ HPLC (method 11): R_(t) = 3.72 min33A

446.54 MS (ESI−), m/z: 445 (M − H)⁻ HPLC (method 17): R_(t) = 4.42 min34A

352.43 MS (ESI−), m/z: 351 (M − H)⁻ HPLC (method 14): R_(t) = 4.61 min35A

416.47 MS (ESI−), m/z: 415 (M − H)⁻ HPLC (method 16): R_(t) = 3.49 min36A

354.44 MS (ESI−), m/z: 353 (M − H)⁻ HPLC (method 16): R_(t) = 3.44 min37A

380.36 MS (ESI−), m/z: 379 (M − H)⁻ HPLC (method 17): R_(t) = 3.72 min38A

434.49 MS (ESI−), m/z: 433 (M − H)⁻ HPLC (method 17): R_(t) = 3.98 min39A

454.52 MS (ESI−), m/z: 453 (M − H)⁻ HPLC (method 22): R_(t) = 4.41 min40A

362.42 MS (ESI−), m/z: 361 (M − H)⁻ HPLC (method 18): R_(t) = 3.74 min41A

355.43 MS (ESI+), m/z: 378 (M + Na)⁺ HPLC (method 19): R_(t) = 4.12 min42A

356.42 MS (ESI−), m/z: 355 (M − H)⁻ HPLC (method 20): R_(t) = 3.64 min43A

427.50 MS (ESI−), m/z: 426 (M − H)⁻ HPLC (method 20): R_(t) = 3.73 min44A

342.39 MS (ESI−), m/z: 341 (M − H)⁻ HPLC (method 19): R_(t) = 4.18 min45A

446.54 MS (ESI−), m/z: 445 (M − H)⁻ HPLC (method 20): R_(t) = 4.02 min46A

381.47 MS (ESI−), m/z: 380 (M − H)⁻ HPLC (method 21): R_(t) = 3.43 min47A

475.54 MS (ESI−), m/z: 474 (M − H)⁻ HPLC (method 20): R_(t) = 3.91 min48A

354.44 MS (ESI−), m/z: 353 (M − H)⁻ HPLC (method 18): R_(t) = 3.80 min49A

340.42 MS (ESI−), m/z: 339 (M − H)⁻ HPLC (method 20): R_(t) = 3.61 min50A

501.58 MS (ESI−), m/z: 500 (M − H)⁻ HPLC (method 21): R_(t) = 3.93 min51A

453.53 MS (ESI−), m/z: 452 (M − H)⁻ HPLC (method 21): R_(t) = 3.61 min52A

430.51 MS (ESI+), m/z: 453 (M + Na)⁺ HPLC (method 20): R_(t) = 4.32 min

In accordance with general instructions A it is possible to obtain thefollowing compounds (Example 53A to 64A):

Example Structure MW MS HPLC 53A

326.40 MS (ESI+), m/z: 349 (M + Na)⁺ HPLC (method 12): R_(t) = 2.97 min54A

352.43 MS (ESI−), m/z: 351 (M − H)⁻ HPLC (method 12): R_(t) = 3.23 min55A

326.39 MS (ESI−), m/z: 325 (M − H)⁻ HPLC (method 5): R_(t) = 3.91 min56A

326.39 MS (ESI−), m/z: 325 (M − H)⁻ HPLC (method 12): R_(t) = 2.88 min57A

326.39 MS (ESI−), m/z: 325 (M − H)⁻ HPLC (method 13): R_(t) = 4.25 min58A

340.42 MS (ESI−), m/z: 339 (M − H)⁻ HPLC (method 17): R_(t) = 3.59 min59A

310.35 MS (ESI−), m/z: 309 (M − H)⁻ HPLC (method 16): R_(t) = 2.41 min60A

328.26 MS (ESI+), m/z: 351 (M + Na)⁺ HPLC (method 20): R_(t) = 3.18 min61A

338.40 MS (ESI−), m/z: 337 (M − H)⁻ HPLC (method 17): R_(t) = 3.57 min62A

340.42 MS (ESI+), m/z: 341 (M + H)⁺ HPLC (method 20): R_(t) = 3.79 min63A

324.38 MS (ESI−), m/z: 323 (M − H)⁻ HPLC (method 19): R_(t) = 4.02 min64A

350.41 MS (ESI−), m/z: 349 (M − H)⁻ HPLC (method 18): R_(t) = 3.66 min

Compound 64A was formed in the course of the reaction of compound 39A.

General Instructions G: Deblocking of Benzyloxycarbonyl-ProtectedHydrazine Derivatives

The benzyloxycarbonyl-protected hydrazine derivative (1 eq.) isdissolved in methanol or ethanol (about 0.05 mol/l), a catalytic amountof palladium-on-carbon (10%) is added and the mixture is stirred under ahydrogen atmosphere (atmospheric pressure) for 3-4 h. The reactionmixture is then filtered and concentrated. The crude product can bereacted without further purification.

In accordance with general instructions G is it possible to obtain thefollowing compounds (Example 65A and 66A):

Example Structure MW MS HPLC 65A

341.41 MS (ESI−), m/z: 340 (M − H)⁻ HPLC (method 19): R_(t) = 4.00 min66A

367.44 MS (ESI−), m/z: 366 (M − H)⁻ HPLC (method 20): R_(t) = 3.47 min

In accordance with general instructions E it is possible to obtain thefollowing compounds (Example 67A to 93A):

Exam- ple Structure MW 67A

226.28 68A

252.32 69A

238.29 70A

226.28 71A

226.28 72A

226.28 73A

240.30 74A

252.32 75A

318.38 76A

210.23 77A

254.33 78A

280.25 79A

228.25 80A

262.31 81A

250.30 82A

255.32 83A

256.30 84A

227.27 85A

242.28 86A

281.36 87A

240.30 88A

241.29 89A

254.33 90A

240.30 91A

267.33 92A

253.30 93A

224.26

Example 94A Methyl (S)-3-amino-3-phenylpropionate

2.3 g (11.65 mmol) of (S)-3-amino-3-phenylpropionic acid are introducedto a vessel in 100 ml of methanol, and a catalytic amount ofconcentrated sulfuric acid (0.02 eq.) is added. The reaction mixture isheated at reflux for 24 h and then concentrated. The crude product canbe used without further purification in the next stage.

Yield: 2.7 g (65% of theory).

¹H-NMR (300 MHz, d₆-DMSO): δ=8.50 (s, 2H), 7.52-7.37 (m, 5H), 4.61 (t,1H), 3.58 (s, 3H), 3.13 (dd, 1H), 2.98 (dd, 1H).

MS (ES+): m/z (%)=180 (M+H)⁺ (100).

General Instructions H: Synthesis of the Beta-Amino Acid Methyl Esters

The beta-amino acid (1 eq) [synthesis in accordance with instructionsknown from the literature, e.g., S. Rault, P. Dallemagne, M. Robba,Bull. Soc. Chim. Fr., 1987, 1079-1083; L. Lázár, T. Martinek, G.Bernáth, F. Fülöp, Synth. Comm., 1998, 28, 219-224] is suspended inmethanol (concentration 0.3-1 mol/l) at temperatures between −40° C. and0° C. Thionyl chloride (2 eq) is added dropwise and the reaction mixtureis warmed to room temperature and stirred overnight. It is evaporated todryness and then the residue is taken up in water and washed twice withethyl acetate. The organic phase is discarded and the aqueous phase isneutralized with saturated sodium hydrogencarbonate solution and againextracted three times with ethyl acetate. The organic phases of thefinal extraction are dried over sodium sulfate or magnesium sulfate,decanted and evaporated to dryness. Alternatively the crude product canbe worked up by dissolving it in a little methanol and recrystallizingthe product by adding diethyl ether.

In accordance with general working instructions H it is possible toprepare the following compounds (Example 95A to 108A):

Structure MW MS HPLC/NMR  95A

180.2 MS (ESI+), m/z: 180 (M + H)⁺  96A

235.3 MS (DCI), m/z: 236 (M + H)⁺  97A

256.3 MS (ESI+), m/z: 257 (M + H)⁺ HPLC (method 5): R_(t) = 3.68 min 98A

248.1 MS (ESI+), m/z: 248 (M + H)⁺  99A

255.3 MS (DCI), m/z: 256 (M + H)⁺ 100A

197.2 MS (DCI), m/z: 198 (M + H)⁺ 101A

209.2 ¹H-NMR (300 MHz, CDCl₃): δ = 2.61-2.68 (m, 2H); 3.69 (s, 3H); 3.80(s, 3H); 4.40 (dd, 1H); 6.80 (dd, 1H); 6.90-6.96 (m, 2H); 7.20-7.29 (m,1H) 102A

221.3 MS (DCI), m/z: 222 (M + H)⁺ 103A

230.3 MS (ESI+), m/z: 231 (M + H)⁺ HPLC (method 20): R_(t) = 1.70 min104A

229.3 MS (ESI+), m/z: 230 (M + H)⁺ HPLC (method 19): R_(t) = 1.75 min105A

185.3 MS (ESI+), m/z: 186 (M + H)⁺ 106A

169.2 MS (ESI+), m/z: 170 (M + H)⁺ 107A

237.3 MS (ESI+), m/z: 238 (M + H)⁺ 108A

223.2 MS (ESI+), m/z: 224 (M + H)⁺

In accordance with general instructions B it is possible to obtain thefollowing compounds (Example 109A to 117A):

Example Structure MW MS HPLC 109A

430.46 MS (ESI+), m/z (%): 431 (M + H)⁺ HPLC (method 12): R_(t) = 2.51min 110A

387.82 MS (ESI+), m/z (%): 388 (M + H)⁺ HPLC (method 12): R_(t) = 3.10min 111A

371.36 MS (ESI+), m/z (%): 372 (M + H)⁺ HPLC (method 17): R_(t) = 3.48min 112A

395.45 MS (ESI+), m/z (%): 396 (M + H)⁺ HPLC (method 17): R_(t) = 3.93min 113A

404.42 MS (ESI+), m/z (%): 405 (M + H)⁺ HPLC (method 19): R_(t) = 2.40min 114A

411.46 MS (ESI+), m/z (%): 412 (M + H)⁺ HPLC (method 20): R_(t) = 3.20min 115A

334.37 MS (ESI+), m/z (%): 335 (M + H)⁺ HPLC (method 18): R_(t) = 3.36min 116A

384.43 MS (ESI+), m/z (%): 385 (M + H)⁺ HPLC (method 21): R_(t) = 3.38min 117A

385.42 MS (ESI+), m/z (%): 386 (M + H)⁺ HPLC (method 21): R_(t) = 2.76min

General Instructions I: Reaction of 3-Aminopropionic Acid Alkyl Esterswith Carbonyl Chlorides

The 3-aminopropionic acid alkyl ester is introduced to a vessel indichloromethane (about 0.1-0.4 mol/l) at RT and 2 to 3 eq. ofdiisopropylethylamine and 1.2 eq. of the carbonyl chloride are added.The mixture is stirred at room temperature for 2 to 3 h. Then water isadded to the reaction mixture and the organic phase is separated off,dried over sodium sulfate, filtered and concentrated. The residue can berecrystallized from dichloromethane and diethyl ether or purified bymeans of chromatography on silica gel (mobile phase: mixtures ofdichloromethane and ethyl acetate).

In accordance with general instructions I it is possible to obtain thefollowing compounds (Example 118A to 122A):

Example Structure MW MS HPLC 118A

443.50 MS (ES+), m/z (%): 444 (M + H)⁺ 119A

375.43 MS (ES+), m/z (%): 376 (M + H)⁺ HPLC (method 9): R_(t) = 4.59 min120A

381.43 MS (ES+), m/z (%): 382 (M + H)⁺ HPLC (method 9): R_(t) = 3.65 min121A

337.42 MS (ES+), m/z (%): 338 (M + H)⁺ HPLC (method 9): R_(t) = 4.52 min122A

413.52 MS (ES+), m/z (%): 414 (M + H)⁺ HPLC (method 9): R_(t) = 4.91 min

In accordance with general instructions C it is possible to obtain thefollowing compounds (Example 123A to 136A):

Example Structure MW MS HPLC 123A

416.43 MS (ESI+), m/z (%): 417 (M + H)⁺ HPLC (method 17): R_(t) = 2.90min 124A

373.79 MS (ESI+), m/z (%): 374 (M + H)⁺ HPLC (method 16): R_(t) = 2.75min 125A

357.34 MS (ESI+), m/z (%): 358 (M + H)⁺ HPLC (method 17): R_(t) = 3.20min 126A

381.43 MS (ESI+), m/z (%): 382 (M + H)⁺ HPLC (method 17): R_(t) = 3.59min 127A

390.39 MS (ESI+), m/z (%): 391 (M + H)⁺ HPLC (method 20): R_(t) = 2.27min 128A

397.43 MS (ESI+), m/z (%): 398 (M + H)⁺ HPLC (method 19): R_(t) = 2.11min 129A

320.35 MS (ESI+), m/z (%): 321 (M + H)⁺ HPLC (method 20): R_(t) = 2.65min 130A

370.41 MS (ESI+), m/z (%): 371 (M + H)⁺ HPLC (method 19): R_(t) = 2.65min 131A

371.39 MS (ESI+), m/z (%): 372 (M + H)⁺ HPLC (method 20): R_(t) = 2.35min 132A

338.37 MS (ESI+), m/z (%): 339 (M + H)⁺ HPLC (method 18): R_(t) = 2.72min 133A

429.48 MS (ES+), m/z (%): 430 (M + H)⁺ HPLC (method 9): R_(t) = 4.31 min134A

361.40 MS (ES+), m/z (%): 362 (M + H)⁺ 135A

309.37 MS (ES+), m/z (%): 310 (M + H)⁺ HPLC (method 9): R_(t) = 4.04 min136A

385.47 MS (ES+), m/z (%): 386 (M + H)⁺

Compound 132A was formed as a by-product during the preparation ofcompound 129A.

The propionic acid derivatives obtained in this way can be reacted inaccordance with general instructions D (acylation of3-[2-aminoalkanoyl]-2,5-Pyrrolidinedione hydrochloride derivatives withcarboxylic acid derivatives).

General Instructions J: Preparation of N-tert-butoxycarbonyl-ProtectedBeta-Amino Acids

The beta-amino acid (1 eq.) [synthesis in accordance with instructionsknown from the literature, e.g., S. Rault, P. Dallemagne, M. Robba,Bull. Soc. Chim. Fr., 1987, 1079-1083; L. Lázár, T. Martinek, G.Bernáth, F. Fülöp, Synth. Comm., 1998, 28, 219-224] is introduced to avessel in water (concentration about 0.3-1 mol/l), and triethylamine(1.5-3 eq.) is added. Then a solution of2-(tert-butoxycarbonyl-oximino)phenylacetonitrile (1.1 eq.) in dioxane(0.3-1 mol/l) is added. The reaction mixture is stirred at roomtemperature for 3 h, diluted with water and washed with diethyl ether.The aqueous phase is acidified with 5% strength citric acid (to a pH ofabout 2) and extracted three times with ethyl acetate. The combinedorganic phases are washed with saturated sodium chloride solution, driedover sodium sulfate, filtered and concentrated. The crude product canoptionally be recrystallized from ethyl acetate/n-hexane.

In accordance with general instructions J it is possible to obtain thefollowing compounds (Example 137A to 150A):

Example Structure MW MS HPLC 137A

310.3 MS (ESI+), m/z: 311 (M + H)⁺ HPLC (method 8): R_(t) = 3.87 min138A

323.34 MS (ESI+), m/z: 324 (M + H)⁺ HPLC (method 8): R_(t) = 2.39 min139A

371.44 MS (ESI+), m/z: 372 (M + H)⁺ HPLC (method 9): R_(t) = 4.47 min140A

295.34 MS (ESI+), m/z: 296 (M + H)⁺ 141A

323.35 HPLC (method 9): R_(t) = 3.96 min 142A

315.37 MS (ESI−), m/z: 314 (M − H)⁻ HPLC (method 21): R_(t) = 3.21 min143A

316.36 MS (ESI+), m/z: 317 (M + H)⁺ HPLC (method 19): R_(t) = 3.47 min144A

295.33 MS (ESI+), m/z: 296 (M + H)⁺ HPLC (method 20): R_(t) = 3.00 min145A

325.36 HPLC (method 9): R_(t) = 3.76 min 146A

266.30 MS (DCI), m/z: 167 (M − 100 + H)⁺ HPLC (method 9): R_(t) = 1.92min 147A

309.32 MS (ESI−), m/z: 308 (M − H)⁻ HPLC (method 13): R_(t) = 3.69 min148A

323.39 MS (ESI−), m/z: 322 (M − H)⁻ HPLC (method 14): R_(t) = 4.35 min149A

295.33 MS (ESI+), m/z: 296 (M + H)⁺ 150A

316.36 MS (ESI+), m/z: 317 (M + H)⁺ HPLC (method 21): R_(t) = 2.14 min

Example 151A (3S)-3-[(tert-Butoxycarbonyl)amino]-3-phenylpropionic Acid

2.82 g (17 mmol) of (S)-3-amino-3-phenylpropionic acid are suspended in60 ml of dioxane and at 0° C. 4.1 g (18.8 mmol) of di-tert-butyldicarbonate (Boc anhydride) and 43 ml of a 1N sodium hydroxide solutionin water are added. The reaction mixture is stirred at 0° C. for another30 minutes and then at room temperature for 3 h. Subsequently thereaction mixture is concentrated and the residue is taken up inmethylene chloride. The organic phase is washed with 1N hydrochloricacid and saturated sodium chloride solution, dried over magnesiumsulfate and concentrated. The crude product (3.12 g) can be reactedfurther without additional purification.

MS (ES−): m/z (%)=264 (M−H)⁻ (100).

HPLC (method 14): R_(t)=3.89 min.

Example 152A (3S)-3-[(tert-Butoxycarbonyl)methylamino]-3-phenylpropionicAcid

500 mg (1.88 mmol) of(3S)-3-[(tert-butoxycarbonyl)amino]-3-phenylpropionic acid areintroduced to a vessel in 6 ml of tetrahydrofuran, and at 0° C. 2.14 g(15.1 mmol) of iodomethane are added. Then 226 mg (5.65 mmol) of a 60%dispersion of sodium hydride in mineral oil are added in portions. Thereaction mixture is warmed to room temperature and stirred overnight.Subsequently 5 ml of water are added cautiously and the reaction mixtureis concentrated. The residue is taken up in ethyl acetate. The organicphase is washed with water, dried over magnesium sulfate, filtered andconcentrated. The crude product (110 mg) can be reacted further withoutadditional purification.

MS (ESI−): m/z=278 (M−H)⁻.

HPLC (method 14): R_(t)=4.27 min.

In accordance with general instructions D it is possible to obtain thefollowing compounds (Example 153A to 170A):

Example Structure MW MS HPLC 153A

517.58 MS (ESI+), m/z: 518 (M + H)⁺ HPLC (method 8): R_(t) = 2.60 min154A

504.54 MS (ESI−), m/z: 503 (M − H)⁻ HPLC (method 6): R₁ = 3.99 min 155A

565.67 MS (ESI+), m/z: 566 (M + H)⁺ HPLC (method 16): R_(t) = 3.45 min156A

489.57 MS (ESI+), m/z: 490 (M + H)⁺ HPLC (method 16): R_(t) = 2.90 min157A

517.58 MS (ESI+), m/z: 518 (M + H)⁺ HPLC (method 16): R_(t) = 2.89 min158A

485.58 MS (ESI−), m/z: 484 (M − H)⁻ HPLC (method 20): R_(t) = 3.72 min159A

487.59 MS (ESI+), m/z: 488 (M + H)⁺ HPLC (method 17): R_(t) = 3.73 min160A

473.57 MS (ESI−), m/z: 472 (M − H)⁻ HPLC (method 12): R_(t) = 3.20 min161A

510.59 MS (ESI−), m/z: 509 (M − H)⁻ HPLC (method 19): R_(t) = 3.99 min162A

509.61 MS (ESI−), m/z: 508 (M − H)⁻ HPLC (method 20): R_(t) = 3.77 min163A

519.60 MS (ESI−), m/z: 518 (M − H)⁻ HPLC (method 18): R_(t) = 3.36 min164A

489.57 MS (ESI−), m/z: 488 (M − H)⁻ HPLC (method 19): R_(t) = 4.19 min165A

489.57 MS (ESI−), m/z: 488 (M − H)⁻ HPLC (method 20): R_(t) = 3.36 min166A

474.56 MS (ESI−), m/z: 473 (M − H)⁻ HPLC (method 19): R_(t) = 2.55 min167A

460.53 MS (ESI+), m/z: 461 (M + H)⁺ HPLC (method 5): R_(t) = 2.86 min168A

517.63 MS (ESI−), m/z: 516 (M − H)⁻ HPLC (method 14): R_(t) = 4.42 min169A

503.56 MS (ESI+), m/z: 504 (M + H)⁺ HPLC (method 14): R_(t) = 4.05 min170A

510.59 MS (ESI+), m/z: 511 (M + H)⁺ HPLC (method 21): R_(t) = 2.50 min

In accordance with general instructions E it is possible to obtain thefollowing compounds (Example 171A to 188A) in the form of theirhydrochlorides:

Ex- ample Structure MW MS HPLC 171A

417.47 MS (ESI−), m/z: 416 (M − H)⁻ HPLC (method 5): R_(t) = 2.23 min172A

404.43 173A

465.55 MS (ESI−), m/z: 464 (M − H)⁻ HPLC method 17): R_(t) = 2.63 min174A

389.46 MS (ESI+), m/z: 390 (M + H)⁺ HPLC method 17): R_(t) = 2.14 and2.25 min 175A

417.47 176A

385.47 MS (ESI−), m/z: 384 (M − H)⁻ HPLC method 20): R_(t) = 1.90 min177A

387.48 178A

373.46 MS (ESI−), m/z: 372 (M − H)⁻ HPLC method 12): R_(t) = 1.33 min179A

410.48 HPLC method 9): R_(t) = 2.79 min 180A

409.49 MS (ESI−), m/z: 408 (M − H)⁻ HPLC method 20): R_(t) = 2.14 + 2.23min 181A

419.48 HPLC method 9): R_(t) = 2.80 min 182A

389.46 MS (ESI−), m/z: 388 (M − H)⁻ HPLC method 19): R_(t) = 3.17 min183A

389.46 HPLC method 9): R_(t) = 2.86 min 184A

374.44 185A

360.42 MS (ESI+), m/z: 361 (M + H)⁺ 186A

417.51 MS (ESI−), m/z: 416 (M − H)⁻ HPLC method 9): R_(t) = 2.97 min187A

403.44 MS (ESI−), m/z: 402 (M − H)⁻ HPLC method 14): R_(t) = 2.40 min188A

410.48

PREPARATION EXAMPLES General Instructions K: Acylation of AcylalkylaminoSubstituted 3-[2-amino-alkanoyl]-2,5-pyrrolidinedione HydrochlorideDerivatives with Carboxylic Acid Derivatives

A mixture of amine hydrochloride (1.0 eq.), carboxylic acid (1.2 to 1.3eq.) and HATU (1.2-1.4 eq.) in solution in absoluteN,N-dimethylformamide or in a 1:1 mixture of N,N-dimethylformamide anddichloromethane (0.02-0.2 mol/l) is admixed at 0° C. with a 0.2-1.0molar solution of diisopropylethylamine (2.5 to 3.5 eq.) inN,N-dimethylformamide or a 1:1 mixture of N,N-dimethylformamide anddichloromethane over a period of 1 h. When the addition is over thereaction mixture is stirred at 0° C. for another 30 minutes and at roomtemperature overnight, and then is concentrated under reduced pressure.The product can be obtained by chromatography on silica gel (mobilephases: mixtures of cyclohexane/ethyl acetate or mixtures ofdichloromethane and ethanol) or by RP-HPLC (mobile phases: variablegradients of water and acetonitrile), or alternatively by a combinationof both methods.

Alternatively the reaction may also take place in accordance with thefollowing method:

A mixture of amine hydrochloride (1.0 eq.), carboxylic acid (1.2 to 1.3eq.), triethylamine (2.4-3 eq.) and HOBt (2.4-3 eq.) in absolutedichloromethane or in a mixture of N,N-dimethylformamide anddichloromethane (0.02-0.2 mol/l) is admixed finally with 1.2 eq. of EDC.The reaction mixture is stirred at room temperature (2 h to overnight)before being concentrated under reduced pressure. The residue is takenup in ethyl acetate or dichloromethane and the organic phase is washedwith water, saturated sodium hydrogencarbonate solution and saturatedsodium chloride solution, dried over sodium sulfate, filtered andconcentrated. The product can be purified by chromatography on silicagel (mobile phases: mixtures of cyclohexane/ethyl acetate or mixtures ofdichloromethane and ethanol) or by RP-HPLC (mobile phases: variablegradients of water and acetonitrile), or alternatively by a combinationof both methods.

General Instructions L: Solid-Phase-Supported Synthesis

The aldehyde resin (Nova Biochem) (0.78 mmol/g) is suspended intoluene/trimethyl orthoformate (1:1 to 4:1), admixed with thecorresponding beta-amino acid methyl ester (2.5-3 eq) at roomtemperature and shaken overnight. The resin is washed twice withN,N-dimethylformamide, suspended in N,N-dimethylformamide and admixedwith tetrabutylammonium borohydride (2-5 eq) at room temperature. After30 minutes of shaking at room temperature the reaction mixture is slowlyadmixed with glacial acetic acid (100 eq) at from −40° C. to roomtemperature, optionally warmed to room temperature again and shaken forat least 1 h. The resin is washed repeatedly with water, methanol,dichlormethane/10% N,N-diisopropylethylamine, methanol, dichloromethaneand diethyl ether and dried. The resin is suspended in dichloromethaneand shaken with N,N-diisopropylethylamine (10-20 eq) and with thecorresponding carbonyl chloride (5 eq) at room temperature for 1-2 h.The resin is washed repeatedly with methanol, N,N-dimethylformamide,methanol, dichloromethane and diethyl ether and dried. For hydrolysisthe resin is admixed with a solution of potassium hydroxide (30 eq) inmethanol/dioxane (1:2, 30 mg potassium hydroxide/ml solution) and shakenat RT for 3 h. Subsequently the resin is washed with water, methanol,dichloromethane/glacial acetic acid, dichloromethane,dichloromethane/N,N-diisopropylethylamine, methanol,N,N-dimethylformamide, methanol, dichloromethane and diethyl ether. Theresin is shaken with (benzotriazol-1-yloxy)bisdimethylaminomethyliumfluoroborate (5 eq) and N,N-diisopropyl-ethylamine (20 eq) inN,N-dimethylacetamide at RT for 1 h, washed twice withN,N-dimethylacetamide, admixed with a freshly prepared solution of(3R,4S)-3-[(2S)-2-amino-3-methylbutanoyl]-4-methyl-2,5-pyrrolidinedionehydrochloride (1.5-2 eq) and N,N-diisopropylethylamine (20 eq) andshaken at RT for 3 h. Finally the resin is washed repeatedly withmethanol, N,N-dimethylformamide, water, N,N-dimethylformamide, methanol,dichloromethane and diethyl ether and dried. The residue is shaken withtrifluoroacetic acid or 50% strength trifluoroacetic acid indichloromethane at from RT to 50° C. for from 30 minutes to 3 h. Thecrude product solution is filtered, evaporated to dryness and purifiedby reversed phase HPLC using a water/acetonitrile gradient. Analternative possibility is chromatography on silica gel (mobile phases:mixtures of dichloromethane and methanol).

In accordance with the above-described instructions for the acylation of3-[2-amino-alkanoyl]-2,5-pyrrolidinedione hydrochloride derivatives(general instructions D) or of acylalkylamino-substituted3-[2-aminoalkanoyl]-2,5-pyrrolidinedione hydrochloride derivatives(general instructions K) with carboxylic acid derivatives or thesolid-phase-supported synthesis (general instructions L) it is possibleto obtain the following compounds.

Example 1(2E)-3-(1,3-Benzodioxol-5-yl)-N-{(1S)-3-[((1S)-2-methyl-1-{[(3R,4S)-4-methyl-2,5-dioxo-3-pyrrolidinyl]carbonyl}propyl)amino]-3-oxo-1-phenylpropyl}-2-propenamide

¹H-NMR (400 MHz, d₆-DMSO): δ=11.34 (s, 1H), 8.44 (d, 1H), 8.12 (d, 1H),7.46-7.38 (m, 5H), 7.35-7.29 (m, 1H), 7.13 (s, 1H), 7.05 (d, 1H), 6.92(d, 1H), 6.50 (d, 1H), 6.07 (s, 2H), 5.47-5.30 (m, 1H), 4.61 (dd, 1H),3.91 (d, 1H), 2.95-2.90 (m, 1H), 2.80 (dd, 1H), 2.69 (dd, 1H), 2.32-2.25(m, 1H), 1.08 (d, 3H), 0.79 (d, 3H), 0.74 (d, 3H).

MS (ESI+): m/z (%)=534 (M+H⁺) (100).

HPLC (method 4): R_(t)=2.34 min.

Example 2(2E)-3-(1,3-Benzodioxol-5-yl)-N-{(1S)-3-[((1S)-2,2-dimethyl-1-{[(3R,4S)-4-methyl-2,5-dioxo-3-pyrrolidinyl]carbonyl}propyl)amino]-3-oxo-1-phenylpropyl}-2-propenamide

¹H-NMR (200 MHz, d₆-DMSO): δ=11.40 (s, 1H), 8.46 (d, 1H), 8.19 (d, 1H),7.35-6.90 (m, 9H), 6.50 (d, 1H), 6.07 (s, 2H), 5.37-5.25 (m, 1H), 4.39(br. d, 1H), 3.85-3.75 (m, 1H), 2.90-2.63 (m, 3H), 1.09 (d, 3H), 0.92(s, 9H).

MS (ESI+): m/z (%)=548 (M+H⁺) (100).

HPLC (method 8): R_(t)=2.45 min.

Example 3(2E)-3-(1,3-Benzodioxol-5-yl)-N-{(1S)-3-[((1S)-1-{[(3R,4S)-1,4-dimethyl-2,5-dioxo-3-pyrrolidinyl]carbonyl}-2-methylpropyl)amino]-3-oxo-1-phenylpropyl}-2-propenamide

¹H-NMR (400 MHz, d₆-DMSO): δ=8.45 (d, 1H), 8.16 (d, 1H), 7.36-7.25 (m,5H), 7.22-7.18 (m, 1H), 7.12 (s, 1H), 7.03 (d, 1H), 6.94 (d, 1H), 6.50(d, 1H), 6.06 (s, 2H), 5.38-5.28 (m, 1H), 4.66 (dd, 1H), 3.88 (d, 1H),3.00-2.92 (m, 1H), 2.82 (s, 3H) 2.78-2.65 (m, 2H), 2.33-2.27 (m, 1H),1.10 (d, 3H), 0.80 (d, 3H), 0.76 (d, 3H).

MS (ESI+): m/z (%)=548 (M+H⁺) (100).

HPLC (method 5): t=2.34 min.

Example 4(2E)-3-(1,1′-Biphenyl-4-yl)-N-{(1S)-3-[((1S)-2-methyl-1-{[(3R,4S)-4-methyl-2,5-dioxo-3-pyrrolidinyl]carbonyl}propyl)amino]-3-oxo-1-phenylpropyl}-2-propenamide

¹H-NMR (400 MHz, d₆-DMSO): δ=11.33 (s, 1H), 8.54 (d, 1H), 8.13 (d, 1H),7.76-7.61 (m, 7H), 7.50-7.21 (m, 8H), 6.70 (s, 2H), 5.40-5.30 (m, 1H),4.63 (dd, 1H), 3.92 (d, 1H), 2.95-2.89 (m, 1H), 2.82 (dd, 1H), 2.70 (dd,1H), 2.32-2.28 (m, 1H), 1.09 (d, 3H), 0.80 (d, 3H), 0.75 (d, 3H).

MS (ESI+): m/z (%)=566 (M+H⁺) (100).

HPLC (method 4): R_(t)=2.68 min.

Example 5(2E)-3-(1,3-Benzodioxol-5-yl)-N-{1-(2,3-dihydro-1,4-benzodioxin-6-yl)-3-[((1S)-2-methyl-1-{[(3R,4S)-4-methyl-2,5-dioxo-3-pyrrolidinyl]carbonyl}propyl)amino]-3-oxopropyl}-2-propenamide

¹H-NMR (2 diastereoisomers, 400 MHz, CDCl₃): δ=8.41 (br. s, 1H), 8.01(br. d, 1H), 7.56-7.48 (m, 1H), 7.01-6.96 (m, 2H), 6.85-6.75 (m, 3H),6.34 (d, 0.5H), 6.28 (d, 0.5H), 6.00 (s, 1H), 5.99 (s, 1H), 5.61-5-59(m, 1H), 5.50-5.46 (m, 1H), 4.81 (dd, 0.5H); 4.70 (dd, 0.5H), 4.20-4.16(m, 4H), 3.98-3.93 (m, 1.5H), 3.48-3.33 (m, 0.5H), 3.30-3.29 (m, 0.5H),2.94-2.88 (m, 1.5H), 2.49-2.35 (m, 1H), 1.24 (d, 1.5H), 1.17 (d, 1.5H),0.93 (d, 1.5H), 0.82 (d, 1.5H), 0.75 (d, 1.5H), 0.69 (d, 1.5H).

MS (ESI+): m/z=592 (M+H⁺).

Example 6(2E)-N-{1-(2,3-Dihydro-1,4-benzodioxin-6-yl)-3-[((1S)-2-methyl-1-{[(3R,4S)-4-methyl-2,5-dioxo-3-pyrrolidinyl]carbonyl}propyl)amino]-3-oxopropyl}-3-phenyl-2-propenamide

MS (ESI+): m/z (%)=548 (M+H⁺) (100).

HPLC (method 9): R_(t)=4.00 min.

Example Structure MW MS HPLC  7

479.53 MS (ES+), m/z (%): 480 (M + H)⁺ (100) HPLC (method 6): Rt = 2.41min  8

490.56 MS (ES+), m/z (%): 491 (M + H)⁺ (100) HPLC (method 6): Rt = 2.83min  9

490.56 MS (ES+), m/z (%): 491 (M + H)⁺ (100) HPLC (method 6): Rt = 2.59min 10

490.56 MS (ES+), m/z (%): 491 (M + H)⁺ (100) HPLC (method 6): Rt = 3.12min 11

495.60 MS (ES+), m/z (%): 496 (M + H)⁺ (100) HPLC (method 6): Rt = 3.74min 12

479.53 MS (ES+), m/z (%): 480 (M + H)⁺ (100) HPLC (method 6): Rt = 3.62min 13

479.53 MS (ES+), m/z (%): 480 (M + H)⁺ (100) HPLC (method 6): Rt = 3.59min 14

489.57 MS (ES+), m/z (%): 490 (M + H)⁺ (100) HPLC (method 6): Rt = 3.83min 15

503.60 MS (ES+), m/z (%): 504 (M + H)⁺ (100) HPLC (method 6): Rt = 4.00min 16

507.56 MS (ES+), m/z (%): 508 (M + H)⁺ (100) HPLC (method 6): Rt = 3.88min 17

507.56 MS (ES+), m/z (%): 508 (M + H)⁺ (100) HPLC (method 6): Rt = 3.88min 18

519.59 MS (ES+), m/z (%): 520 (M + H)⁺ (100) HPLC (method 6): Rt = 3.86min 19

519.59 MS (ES+), m/z (%): 520 (M + H)⁺ (100) HPLC (method 6): Rt = 3.81min 20

524.01 MS (ES+), m/z (%): 524 (M + H)⁺ (100) HPLC (method 6): Rt = 4.07min 21

524.01 MS (ES+), m/z (%): 524 (M + H)⁺ (100) HPLC (method 6): Rt = 4.06min 22

524.01 MS (ES+), m/z (%): 524 (M + H)⁺ (100) HPLC (method 6): Rt = 4.00min 23

549.62 MS (ES+), m/z (%): 550 (M + H)⁺ (100) HPLC (method 6): Rt = 3.81min 24

549.62 MS (ES+), m/z (%): 550 (M + H)⁺ (100) HPLC (method 6): Rt = 3.64min 25

549.62 MS (ES+), m/z (%): 550 (M + H)⁺ (100) HPLC (method 6): Rt = 3.90min 26

557.57 MS (ES+), m/z (%): 558 (M + H)⁺ (100) HPLC (method 6): Rt = 4.17min 27

558.46 MS (ES+), m/z (%): 558 (M + H)⁺ (100) HPLC (method 6): Rt = 4.29min 28

515.61 MS (ES+), m/z (%): 516 (M + H)⁺ (100) HPLC (method 6): Rt = 4.11min 29

519.55 MS (ES+), m/z (%): 520 (M + H)⁺ (100) HPLC (method 5): Rt = 3.63min 30

547.60 MS (ES+), m/z (%): 548 (M + H)⁺ (100) HPLC (method 5): Rt = 3.98min

Example 31(2E)-3-(2H-Benzo[d]1,3-dioxolan-5-yl)-N-((1S)-2-{N-[(1S)-2-((4S,3R)-4-methyl-2,5-dioxoazolidin-3-yl)-1-cyclopentyl-2-oxoethyl]carbamoyl}-1-phenylethyl)prop-2-enamide

¹H-NMR (400 MHz, d₆-DMSO): δ=11.33 (s, 1H), 8.49 (br. s, 1H), 8.40 (br.d, 1H), 7.37-7.18 (m, 6H), 7.12 (s, 1H), 7.04 (d, 1H), 6.93 (d, 1H),6.51 (d, 1H), 6.06 (s, 2H), 5.48-5.27 (m, 1H), 4.52 (t, 1H), 3.89 (m,1H), 2.91-2.78 (m, 2H), 2.69-2.60 (m, 1H), 2.48-2.27 (m, 1H), 1.60-1.32(m, 6H), 1.26-1.03 (m, 3H), 1.05 (d, 2H).

MS (ESI+): m/z=560 (M+H⁺).

HPLC (method 22): R_(t)=4.15 min.

Example 32(2E)-N-((1S)-2-{N-[(1S)-2-((4S,3R)-4-methyl-2,5-dioxoazolidin-3-yl)-1-cyclopentyl-2-oxoethyl]carbamoyl}-1-phenylethyl)-3-(2,2-difluorobenzo[3,4-d]1,3-dioxolen-5-yl)prop-2-enamide

¹H-NMR (200 MHz, d₆-DMSO): δ=11.34 (s, 1H), 8.57 (br. s, 1H), 8.29 (br.d, 1H), 7.63 (s, 1H), 7.50-7.12 (m, 7H), 6.67 (br. d, 1H), 5.43-5.24 (m,1H), 4.63-4.41 (m, 1H), 4.40-4.20 (m, 1H), 3.88 (d, 1H), 2.97-2.57 (m,3H), 2.41-2.12 (m, 1H), 1.54-1.28 (m, 6H), 1.28-0.97 (m, 5H).

MS (ESI+): m/z 596.3 (M+H⁺).

HPLC (method 19): R_(t)=4.24 min.

Example 33(2E)-N-((1S)-2-{N-[(1S)-2-((4S,3R)-4-methyl-2,5-dioxoazolidin-3-yl)-1-cyclopentyl-2-oxoethyl]carbamoyl}1-phenylethyl)-3-(4-cyanophenyl)prop-2-enamide

¹H-NMR (300 MHz, d₆-DMSO): δ=11.31 (s, 1H), 8.70-8.56 (m, 1H), 8.27 (d,1H), 7.87 (d, 2H), 7.72 (d, 2H), 7.50-7.16 (m, 6H), 6.80 (d, 1H), 5.34(dd, 1H), 4.57-4.22 (m, 1H), 3.87 (m, 1H), 2.93-2.61 (m, 3H), 2.46-2.17(m, 2H), 1.61-1.29 (m, 6H), 1.28-0.96 (m, 4H).

MS (ESI+): m/z=541 (M+H⁺).

HPLC (method 19): R_(t)=4.10 min.

Example 34(2E)-N-((1S)-2-{N-[(1S)-2-((4S,3R)-1-amino-4-methyl-2,5-dioxoazolidin-3-yl)-1-cyclopentyl-2-oxoethyl]carbamoyl}-1-phenylethyl)-3-(4-cyanophenyl)prop-2-enamide

¹H-NMR (300 MHz, d₆-DMSO): δ=8.72-8.57 (m, 1H), 8.54-8.23 (m, 1H), 7.88(d, 2H), 7.72 (d, 2H), 7.45 (d, 1H), 7.39-7.16 (m, 5H), 6.81 (d, 1H),5.43-5.27 (m, 1H), 4.53-4.31 (m, 1H), 3.71 (d, 1H), 2.94-2.63 (m, 3H),2.42-2.23 (m, 2H), 2.04-1.93 (m, 1H), 1.67-1.32 (m, 6H), 1.21-1.02 (m,5H).

MS (ESI+): m/z=556 (M+H⁺).

HPLC (method 19): R_(t)=4.08 min.

Ex- ample Structure MW MS HPLC  35

539.61 MS (ESI+), m/z: 540 (M + H)⁺ HPLC (method 9): R_(t) = 3.97 min 36

495.60 MS (ESI+), m/z: 496 (M + H)⁺ HPLC (method 9): R_(t) = 4.04 min 37

490.56 MS (ESI+), m/z: 491 (M + H)⁺ HPLC (method 5): R_(t) = 2.74 and2.78 min  38

566.66 MS (ESI+), m/z: 567 (M + H)⁺ HPLC (method 5): R_(t) = 3.37 min 39

623.70 MS (ESI+), m/z: 624 (M + H)⁺ HPLC (method 5): R_(t) = 4.30 min 40

579.69 MS (ESI+), m/z: 580 (M + H)⁺ HPLC (method 9): R_(t) = 4.60 min 41

503.60 MS (ESI+), m/z: 504 (M + H)⁺ HPLC (method 9): R_(t) = 4.19 min 42

555.63 MS (ESI+), m/z: 556 (M + H)⁺ HPLC (method 9): R_(t) = 4.40 min 43

623.70 MS (ESI+), m/z: 624 (M + H)⁺ HPLC (method 9): R_(t) = 4.45 min 44

621.77 MS (ESI+), m/z: 622 (M + H)⁺ HPLC (method 5): R_(t) = 5.01 min 45

642.75 MS (ESI+), m/z: 643 (M + H)⁺ HPLC (method 5): R_(t) = 4.21 min 46

634.56 MS (ESI+), m/z: 634 (M + H)⁺ HPLC (method 5): R_(t) = 4.79 min 47

580.12 MS (ESI+), m/z: 580 (M + H)⁺ HPLC (method 5): R_(t) = 4.77 min 48

601.11 MS (ESI+), m/z: 600 (M + H)⁺ HPLC (method 5): R_(t) = 4.65 min 49

601.10 MS (ESI+), m/z: 601 (M + H)⁺ HPLC (method 14): R_(t) = 4.13 min 50

547.61 MS (ESI+), m/z: 548 (M + H)⁺ HPLC (method 12): R_(t) = 2.92 min 51

591.66 MS (ESI+), m/z: 592 (M + H)⁺ HPLC (method 14): R_(t) = 4.39 min 52

577.59 MS (ESI+), m/z: 578 (M + H)⁺ HPLC (method 10): R_(t) = 2.88 min 53

591.61 MS (ESI+), m/z: 592 (M + H)⁺ HPLC (method 14): R_(t) = 4.25 min 54

547.61 MS (ESI+), m/z: 548 (M + H)⁺ HPLC (method 6): R_(t) = 3.84 min 55

547.61 MS (ESI+), m/z: 570 (M + Na)⁺ HPLC (method 13): R_(t) = 4.13 min 56

547.61 MS (ESI+), m/z: 548 (M + H)⁺ HPLC (method 12): R_(t) = 2.99 min 57

610.66 MS (ESI+), m/z: 611 (M + H)⁺ HPLC (method 12): R_(t) = 2.45 min 58

639.70 MS (ESI+), m/z: 640 (M + H)⁺ HPLC (method 12): R_(t) = 3.50 min 59

568.02 MS (ESI+), m/z: 568 (M + H)⁺ HPLC (method 16): R_(t) = 2.99 min 60

578.58 MS (ESI+), m/z: 579 (M + H)⁺ HPLC (method 9): R_(t) = 4.06 min 61

569.56 MS (ESI+), m/z: 570 (M + H)⁺ HPLC (method 14): R_(t) = 4.47 min 62

531.56 MS (ESI+), m/z: 532 (M + H)⁺ HPLC (method 16): R_(t) = 2.65 min 63

575.66 MS (ESI+), m/z: 576 (M + H)⁺ HPLC (method 16): R_(t) = 3.29 min 64

561.63 MS (ESI+), m/z: 562 (M + H)⁺ HPLC (method 16): R_(t) = 3.06 min 65

573.64 MS (ESI+), m/z: 574 (M + H)⁺ HPLC (method 17): R_(t) = 3.72 min 66

591.61 MS (ESI+), m/z: 592 (M + H)⁺ HPLC (method 14): R_(t) = 4.33 min 67

623.70 MS (ESI+), m/z: 624 (M + H)⁺ HPLC (method 17): R_(t) = 3.92 min 68

601.58 MS (ESI+), m/z: 602 (M + H)⁺ HPLC (method 17): R_(t) = 3.68 min 69

507.56 MS (ESI+), m/z: 508 (M + H)⁺ HPLC (method 17): R_(t) = 3.64 min 70

552.07 MS (ESI+), m/z: 552 (M + H)⁺ HPLC (method 18): R_(t) = 3.84 min 71

517.62 MS (ESI+), m/z: 518 (M + H)⁺ HPLC (method 18): R_(t) = 3.74 min 72

553.60 MS (ESI+), m/z: 554 (M + H)⁺ HPLC (method 18): R_(t) = 3.83 min 73

547.65 MS (ESI+), m/z: 548 (M + H)⁺ HPLC (method 18): R_(t) = 3.75 min 74

577.61 MS (ESI+), m/z: 578 (M + H)⁺ HPLC (method 18): R_(t) = 3.45 min 75

601.70 MS (ESI+), m/z: 602 (M + H)⁺ HPLC (method 18): R_(t) = 3.62 min 76

532.64 MS (ESI+), m/z: 533 (M + H)⁺ HPLC (method 17): R_(t) = 3.45 min 77

503.60 MS (ESI+), m/z: 504 (M + H)⁺ HPLC (method 17): R_(t) = 3.57 min 78

636.70 MS (ESI+), m/z: 637 (M + H)⁺ HPLC (method 17): R_(t) = 3.27 min 79

579.62 MS (ESI+), m/z: 580 (M + H)⁺ HPLC (method 17): R_(t) = 3.72 min 80

603.72 MS (ESI+), m/z: 604 (M + H)⁺ HPLC (method 17): R_(t) = 4.09 min 81

533.60 MS (ESI+), m/z: 534 (M + H)⁺ HPLC (method 22): R_(t) = 4.10 min 82

550.05 MS (ESI+), m/z: 550 (M + H)⁺ HPLC (method 19): R_(t) = 4.22 min 83

549.58 MS (ESI+), m/z: 550 (M + H)⁺ HPLC (method 19): R_(t) = 4.02 min 84

583.64 MS (ESI+), m/z: 584 (M + H)⁺ HPLC (method 18): R_(t) = 3.70 min 85

571.63 MS (ESI+), m/z: 572 (M + H)⁺ HPLC (method 20): R_(t) = 3.59 min 86

638.72 MS (ESI+), m/z: 639 (M + H)⁺ HPLC (method 20): R_(t) = 3.39 min 87

576.65 MS (ESI+), m/z: 577 (M + H)⁺ HPLC (method 20): R_(t) = 3.60 min 88

564.08 MS (ESI+), m/z: 564 (M + H)⁺ HPLC (method 18): R_(t) = 3.90 min 89

577.63 MS (ESI+), m/z: 578 (M + H)⁺ HPLC (method 20): R_(t) = 3.73 min 90

548.59 MS (ESI+), m/z: 549 (M + H)⁺ HPLC (method 21): R_(t) = 2.96 min 91

545.59 MS (ESI+), m/z: 546 (M + H)⁺ HPLC (method 20): R_(t) = 3.37 min 92

583.64 MS (ESI+), m/z: 584 (M + H)⁺ HPLC (method 19): R_(t) = 4.25 min 93

557.65 MS (ESI+), m/z: 558 (M + H)⁺ HPLC (method 19): R_(t) = 4.08 min 94

526.59 MS (ESI+), m/z: 527 (M + H)⁺ HPLC (method 20): R_(t) = 3.48 min 95

563.60 MS (ESI+), m/z: 564 (M + H)⁺ HPLC (method 20): R_(t) = 3.46 min 96

593.63 MS (ESI+), m/z: 594 (M + H)⁺ HPLC (method 20): R_(t) = 3.16 min 97

660.77 MS (ESI+), m/z: 661 (M + H)⁺ HPLC (method 21): R_(t) = 3.10 min 98

561.63 MS (ESI+), m/z: 562 (M + H)⁺ HPLC (method 19): R_(t) = 4.19 min 99

562.62 MS (ESI+), m/z: 563 (M + H)⁺ HPLC (method 19): R_(t) = 4.14 min100

514.58 MS (ESI+), m/z: 515 (M + H)⁺ HPLC (method 19): R_(t) = 4.00 min101

543.62 MS (ESI+), m/z: 544 (M + H)⁺ HPLC (method 21): R_(t) = 3.09 min102

539.63 MS (ESI+), m/z: 540 (M + H)⁺ HPLC (method 19): R_(t) = 4.12 min103

529.59 MS (ESI+), m/z: 530 (M + H)⁺ HPLC (method 18): R_(t) = 3.17 min104

514.58 MS (ESI+), m/z: 515 (M + H)⁺ HPLC (method 18): R_(t) = 3.30 min105

575.66 MS (ESI+), m/z: 576 (M + H)⁺ HPLC (method 21): R_(t) = 3.52 min106

633.75 MS (ESI+), m/z: 634 (M + H)⁺ HPLC (method 20): R_(t) = 3.33 min107

583.69 MS (ESI+), m/z: 584 (M + H)⁺ HPLC (method 18): R_(t) = 3.58 min108

569.66 MS (ESI+), m/z: 570 (M + H)⁺ HPLC (method 19): R_(t) = 2.76 min109

540.62 MS (ESI+), m/z: 541 (M + H)⁺ HPLC (method 20): R_(t) = 3.19 min110

561.63 MS (ESI+), m/z: 562 (M + H)⁺ HPLC (method 18): R_(t) = 3.58 min111

491.55 MS (ESI+), m/z: 492 (M + H)⁺ HPLC (method 20): R_(t) = 2.68 min112

514.58 MS (ESI+), m/z: 515 (M + H)⁺ HPLC (method 20): R_(t) = 3.25 min113

546.62 MS (ESI+), m/z: 547 (M + H)⁺ HPLC (method 20): R_(t) = 2.86 min114

563.60 MS (ESI+), m/z: 564 (M + H)⁺ HPLC (method 20): R_(t) = 3.28 min115

605.69 MS (ESI+), m/z: 606 (M + H)⁺ HPLC (method 19): R_(t) = 2.85 min116

521.62 MS (ESI+), m/z: 522 (M + H)⁺ HPLC (method 20): R_(t) = 2.59 min117

584.63 MS (ESI+), m/z: 585 (M + H)⁺ HPLC (method 21): R_(t) = 2.81 min118

565.63 MS (ESI+), m/z: 566 (M + H)⁺ HPLC (method 19): R_(t) = 2.29 min119

532.59 MS (ESI+), m/z: 533 (M + H)⁺ HPLC (method 21): R_(t) = 2.58 min120

565.63 MS (ESI+), m/z: 566 (M + H)⁺ HPLC (method 19): R_(t) = 2.12 min

Example 1214-(1-((2E)-3-(2H-Benzo[3,4-d]1,3-dioxolen-5-yl)prop-2-enoylamino)-2-{N-[(1S)-2-((4S,3R)-4-methyl-2,5-dioxoazolidin-3-yl)-1-(methylethyl)-2-oxoethyl]carbamoyl}-ethyl)benzoicAcid

The benzoic acid methyl ester of Example 53 (240 mg, 0.41 mmol) isdissolved in 10 ml of a dioxane/water (1/1) mixture and the solution isadmixed with 50 mg (0.89 mol) of potassium hydroxide. After 2 h at roomtemperature a further 25 mg of potassium hydroxide are added andstirring is continued for 3 h more. The reaction mixture is concentratedand the residue is taken up in water and acidified with 1 N hydrochloricacid. The product is obtained in crystalline form and is isolated byfiltration. This gives 96 mg of product.

MS (ESI+): m/z=578 (M+H⁺).

HPLC (method 14): R_(t)=3.68 min.

General Instructions M: Preparation of Benzoic Esters

The benzoic acid derivative of Example 121 is dissolved indichloromethane and the solution is admixed with 2 to 3 eq. of thecorresponding alcohol. Alternatively the alcohol can be used as solvent.2.2 eq. of 4-dimethylaminopyridine and 1.1 eq. of EDC are added to thesolution. The reaction mixture is stirred at room temperature overnightand concentrated. The product can then be crystallized from the residueby treatment with dichloromethane and diethyl ether. The product ispurified further by chromatography on silica gel usingdichloromethane/methanol mixtures.

In accordance with general instructions M it is possible to obtain thefollowing compounds (Example 122 and 123):

Ex- ample Structure MW MS HPLC 122

667.71 MS (ESI+), m/z: 668 (M + H)⁺ HPLC (method 14): R_(t) = 4.52 min123

605.64 MS (ESI+), m/z: 606 (M + H)⁺ HPLC (method 14): R_(t) = 4.22 min

General Instructions N: Acylation of N-aminopyrrolidinedione Derivatives

The N-aminopyrrolidinedione derivative is dissolved in pyridine (about0.1 mol/l) and the solution is admixed with 1.1 eq of the correspondingcarbonyl chloride. The reaction mixture is stirred at room temperatureovernight and concentrated under reduced pressure. The residue isadmixed with water and dichloromethane and filtered over Extrelut. Theorganic phase is concentrated and the crude product is purified bychromatography on silica gel using dichloromethane/ethanol mixtures.

In accordance with general instructions N it is possible to obtain thefollowing compounds (Example 124 to 126):

Ex- ample Structure MW MS HPLC 124

590.63 MS (ESI+), m/z: 591 (M + H)⁺ HPLC (method 19): R_(t) = 2.59 min125

652.70 MS (ESI+), m/z: 653 (M + H)⁺ HPLC (method 21): R_(t) = 3.30 min126

666.73 MS (ESI+), m/z: 667 (M + H)⁺ HPLC (method 19): R_(t) = 2.78 min

B) EVALUATION OF PHYSIOLOGICAL ACTIVITY

The suitability of the compounds of the invention for treating bacterialdiseases can be demonstrated in the following animal models:

Determination of the Minimum Inhibitory Concentration (MIC):

The MIC is determined in a liquid dilution test. Overnight cultures ofthe test organisms are diluted to a cell count of 10⁵ organisms per mlin Isosensitest medium (Difco, Irvine, USA) and are incubated withdilutions of the test substances (1:2 dilution stages). Exceptions arethe tests with S. pneumoniae G9A, which are conducted in BHI broth(Difco) plus 20% bovine serum, and with H. influenzae, which areconducted in BHI broth (Difco) plus 20% bovine serum, 10 μg/ml hemin and1% Isovitale (Becton Dickinson, New Jersey, USA).

The cultures are incubated at 37° C. for 18-24 hours; S. pneumoniae andH. influenzae in the presence of 8-10% CO₂.

Results:

The lowest concentration of each substance at which there is no longerany visible bacterial growth is defined as the MIC. The MICs in μmol/lof some compounds of the invention against a series of test organismsare listed by way of example in the table below.

Staphylococcus Haemophilus influenzae Ex. No. aureus 133 Spain 7 1 3.931.3 2 7.8 31.3 5 7.8 3.9 11 7.8 62.5 31 <1 31.3 34 <1 7.8 92 <1 15.6Systemic Infection with S. aureus 133

S. aureus 133 cells are cultured overnight in BH broth (Oxoid, New York,USA). The overnight culture is diluted 1:100 in fresh BH broth and spunat high speed for 3 hours. The bacteria in the logarithmic growth phaseare centrifuged off and washed 2× with buffered physiological salinesolution. Subsequently a photometer (Dr. Lange model LP 2W, Berlin,Germany) is used to establish a cell suspension in saline solution withan extinction of 50 units. Following a dilution step (1:15) thissuspension is mixed 1:1 with a 10% mucin suspension. 0.25 ml/20 g mouseof this infection solution is administered intraperitoneally. Thiscorresponds to a cell count of approximately 1×10E⁶ organisms/mouse. Theintraperitoneal or intravenous therapy is practiced 30 minutes followinginfection. Female CFW1 mice are used for the infection experiment. Thesurvival of the animals is recorded over 6 days.

C) EXAMPLES OF PHARMACEUTICAL COMPOSITIONS

The substances of the invention can be converted into pharmaceuticalformulations as follows:

Tablet: Composition:

100 mg of the compound from Example 1, 50 mg of lactose (monohydrate),50 mg of corn starch, 10 mg of polyvinylpyrolidone (PVP 25) (BASF,Germany) and 2 mg of magnesium stearate.

Tablet weight 212 mg. Diameter 8 mm, radius of curvature 12 mm.

Production:

The mixture of the compound of Example 1, lactose and starch isgranulated with a 5% strength solution (m/m) of the PVP in water. Thegranules are dried and then mixed with the magnesium stearate for 5minutes. This mixture is compressed using a conventional tablet press(see above for tablet format).

Oral Suspension: Composition:

1000 mg of the compound from Example 1, 1000 mg of ethanol (96%), 400-mgof Rhodigel (xanthan gum) (FMC, USA) and 99 g of water.

10 ml of oral suspension correspond to a single dose of 100 mg of thecompound of the invention.

Production:

The Rhodigel is suspended in ethanol and the compound of Example 1 isadded to the suspension. The water is added with stirring. The mixtureis stirred for about 6 h until the Rhodigel has finished swelling.

Solution for Intravenous Administration: Composition:

100-200 mg of the compound from Example 1, 15 g of polyethylene glycol400 and 250 g of injection-grade water.

Production:

The compound of Example 1 is dissolved together with polyethylene glycol400 in the water, with stirring. The solution is subjected to sterilefiltration (pore diameter 0.22 μm) and dispensed under asepticconditions into heat-sterilized infusion bottles. These bottles aresealed with infusion stoppers and crimped caps.

1. A compound of the formula (I),

in which R¹ is hydrogen, methyl or halogen; R^(1′) is hydrogen, methylor halogen; R² is hydrogen or methyl; R³ is hydrogen, hydroxyl, amino,C₁-C₃ alkyl, C₁-C₃ alkoxy, benzyloxy, C₁-C₃ alkylamino, C₁-C₃alkylcarbonylamino, phenylcarbonylamino or benzyl-carbonylamino R⁴ ishydrogen or C₁-C₃ alkyl; n is 2 or 3, when n is 2: two substituents R⁵together with the carbon atoms to which they are attached form a dioxinering fused to the B ring, which may be substituted by 0, 1 or 2substituents R⁵⁻¹, the substituents R⁵⁻¹ being selected independently ofone another from the group consisting of halogen, nitro, amino,trifluoromethyl, hydroxyl and alkoxy; when n is 3: one substitutent R⁵is halogen, trifluoromethyl, trifluoromethoxy, nitro, amino, alkylamino,hydroxyl, alkyl, alkoxy, carboxyl, alkoxycarbonyl, benzyloxycarbonyl,aminocarbonyl, alkylaminocarbonyl, aryl or heteroaryl, and twosubstituents R⁵ together with the carbon atoms to which they areattached form a dioxine ring fused to the B ring, which may besubstituted by 0, 1 or 2 substituents R⁵⁻¹, the substituents R⁵⁻¹ beingselected independently of one another from the group consisting ofhalogen, nitro, amino, trifluoromethyl, hydroxyl and alkoxy; R⁶ isalkyl, cycloalkyl or cycloalkenyl; it being possible for R⁶ to besubstituted by 0, 1, 2 or 3 substituents R⁶⁻¹, the substituents R⁶⁻¹being selected independently of one another from the group consisting ofhalogen, nitro, amino, trifluoromethyl, hydroxyl, alkyl and alkoxy; m isa number 1, 2 or 3; A is aryl or heteroaryl, it being possible for A tobe substituted by 0, 1, 2 or 3 substituents R^(A), the substituentsR^(A) being selected independently of one another from the groupconsisting of halogen, alkyl, nitro, amino, cyano, trifluoromethyl,aryl, heteroaryl, hydroxyl, alkoxy, alkyl-amino, carboxyl,alkoxycarbonyl, aminocarbonyl, alkyl-carbonylamino andalkyl-amino-carbonyl, or two substituents R^(A) together with the carbonatoms to which they are attached form a dioxolane ring fused to the Aring, which may be substituted by 0, 1 or 2 substituents R^(A-1), thesubstituents R^(A-1) being selected independently of one another fromthe group consisting of halogen, nitro, amino, trifluoromethyl, hydroxyland alkoxy; B is aryl or heteroaryl; or a pharmaceutically acceptablesalt, solvate or hydrate thereof. 2-20. (canceled)
 21. A compound asclaimed in claim 1, characterized in that R¹ is hydrogen or methyl;R^(1′) is hydrogen, methyl or fluorine; R² is hydrogen; R³ is hydrogen,amino, C₁-C₃ alkyl, C₁-C₃ alkoxy, benzyloxy, C₁-C₃ alkylamino, C₁-C₃alkylcarbonylamino, phenylcarbonylamino or benzylcarbonylamino; R⁴ ismethyl; two substituents R⁵ together with the carbon atoms to which theyare attached form a dioxine ring fused to the B ring; R⁶ is C₂-C₇ alkyl,C₃-C₇ cycloalkyl or C₅-C₇ cycloalkenyl, it being possible for R⁶ to besubstituted by 0, 1 or 2 substituent R⁶⁻¹, R⁶⁻¹ being selected from thegroup consisting of halogen, trifluoromethyl, alkyl and methoxy, m is anumber 1 or 2; A is phenyl, naphthyl or 5-, 6- or 10-memberedheteroaryl, it being possible for A to be substituted by 0, 1 or 2substituents R^(A), the substituents R^(A) being selected independentlyof one another from the group consisting of halogen, alkyl, amino,cyano, trifluoromethyl, aryl, heteroaryl, hydroxyl, alkoxy, alkylamino,alkoxycarbonyl and aminocarbonyl, or two substituents R^(A) togetherwith the carbon atoms to which they are attached form a dioxolane ringfused to the R^(A) ring, which may be substituted by 0 or 1 substituentsR^(A-1), the substituents R^(A-1) being selected independently of oneanother from the group consisting of halogen, nitro, amino,trifluoromethyl, hydroxyl and alkoxy; B is phenyl, naphthyl or 5-, 6-,9- or 10-membered heteroaryl.
 22. A compound as claimed in one of claims1 or 21, characterized in that it conforms to formula (Ia)

in which R¹ is hydrogen; R^(1′) is hydrogen, methyl or fluorine; R² ishydrogen; R³ is hydrogen, amino, methyl, methoxy, ethoxy, methylamino ordimethylamino; R⁴ is methyl; n is 2; two substituents R⁵ together withthe carbon atoms to which they are attached form a dioxine ring fused tothe B ring; R⁶ is C₃-C₆ alkyl, C₄-C₆ cycloalkyl or C₅-C₆ cycloalkenyl; mis the number 1; A is phenyl, pyridyl, imidazolyl, thienyl, furanyl,oxadiazolyl, pyrazolyl, pyrazinyl, pyridazinyl, pyrimidinyl, quinolinylor isoquinolinyl, it being possible for A to be substituted by 0, 1 or 2substituents R^(A), the substituents R^(A) being selected independentlyof one another from the group consisting of halogen, alkyl, cyano,trifluoromethyl, phenyl and alkoxy, or two substituents R^(A) togetherwith the carbon atoms to which they are attached form a dioxolane ringfused to the A ring; B is phenyl, naphthyl, pyridyl, thienyl, furanyl,quinolinyl or isoquinolinyl.
 23. A compound as claimed in claim 22,characterized in that R¹ is hydrogen; R^(1′) is hydrogen; R² ishydrogen; R³ is hydrogen, amino, methylamino or dimethylamino; R⁴ ismethyl; n is 2; two substituents R⁵ together with the phenyl ring towhich they are attached form a 1,3-benzodioxole or a 1,4-benzodioxane;R⁶ is isopropyl, tert-butyl, isobutyl, isopentyl, cyclobutyl orcyclopentyl; m is the number 1; A is phenyl, pyridyl, thienyl,quinolinyl or isoquinolinyl, it being possible for A to be substitutedby 0, 1 or 2 substituents R^(A), the substituents R^(A) being selectedindependently of one another from the group consisting of fluorine,chlorine, C₁-C₃ alkyl, cyano, trifluoromethyl, phenyl and C₁-C₃ alkoxy,or two substituents R^(A) together with the phenyl ring to which theyare attached form a 1,3-benzodioxole or a 1,4-benzodioxane; B is phenyl,naphthyl, thienyl, quinolinyl or isoquinolinyl.
 24. A compound asclaimed in one of claims 1 or 21, characterized in that R¹ is hydrogen.25. A compound as claimed in claim 1, characterized in that R^(1′) ishydrogen.
 26. A compound as claimed in claim 1, characterized in that R²is hydrogen.
 27. A compound as claimed in claim 1, characterized in thatR⁴ is methyl.
 28. A compound as claimed in claim 1, characterized inthat m is the number
 1. 29. A compound as claimed in claim 1,characterized in that R³ is hydrogen or amino.
 32. A compound as claimedin claim 1, characterized in that R⁶ is isopropyl, tert-butyl, isobutyl,isopentyl or cyclopentyl.
 33. A compound as claimed in claim 1,characterized in that A is phenyl or pyridyl, it being possible for A tobe substituted by 0, 1 or 2 substituents R^(A), the substituents R^(A)being selected independently of one another from the group consisting offluorine, chlorine, cyano, trifluoromethyl, phenyl and methoxy.
 34. Aprocess for preparing compounds as claimed in claim 1, characterized inthat by process [A] a compound of the formula

in which R² to R⁶, B and n are as defined in claim 1, is reacted with acompound of the formula

in which R¹ and R^(1′), A and m are as defined in claim 1, it beingpossible for these to be in activated form if desired, or by process [B]a compound of the formula

in which R³, R⁴ and R⁶ are as defined in claim 1 is reacted with acompound of the formula

in which R¹, R^(1′), R², R⁵, A, B, m and n are as defined in claim 1, itbeing possible for these to be in activated form if desired.
 35. Apharmaceutical composition comprising at least one compound as claimedin claim 1 in combination with at least one pharmaceutically acceptablecarrier or excipient.
 36. A method of treating a bacterial infection ina person or animal comprising administering to said person or animal anantibacterially effective amount of at least one compound of claim 1.